{"gene":"ACIN1","run_date":"2026-06-09T22:02:38","timeline":{"discoveries":[{"year":1999,"finding":"Acinus (ACIN1) is a nuclear factor that induces apoptotic chromatin condensation after proteolytic cleavage by caspase-3, without inducing DNA fragmentation. Immunodepletion experiments showed Acinus is essential for apoptotic chromatin condensation in vitro.","method":"In vitro reconstitution system, immunodepletion, antisense knockdown","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with immunodepletion and antisense confirmation; foundational study replicated by multiple subsequent labs","pmids":["10490026"],"is_preprint":false},{"year":2005,"finding":"Akt directly phosphorylates Acinus on serine 422 and serine 573, making Acinus resistant to caspase cleavage in the nucleus and inhibiting Acinus-dependent chromatin condensation. Phosphomimetic mutant (S422,573D) resists apoptotic cleavage; unphosphorylatable mutant accelerates chromatin condensation. Nuclear Akt depletion provokes apoptotic cleavage of Acinus.","method":"In vitro kinase assay, site-directed mutagenesis, siRNA knockdown, cell-based apoptosis assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct kinase assay with mutagenesis plus cell-based validation; multiple orthogonal methods in single study","pmids":["16177823"],"is_preprint":false},{"year":2006,"finding":"Knockdown of Acinus isoforms by inducible RNAi does not inhibit apoptotic chromatin condensation but does reduce oligonucleosomal DNA fragmentation, indicating Acinus contributes to internucleosomal DNA cleavage rather than chromatin condensation during apoptosis. Acinus is not required for nuclear localization of ASAP complex subunits SAP18 and RNPS1.","method":"Inducible RNAi stable knockdown, cell-free apoptosis system, DNA fragmentation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean inducible RNAi with both intact-cell and cell-free system readouts; contradicts original chromatin condensation claim with rigorous controls","pmids":["16537548"],"is_preprint":false},{"year":2007,"finding":"The caspase-cleaved active Acinus p17 fragment promotes apoptotic chromatin condensation by binding to both Mst1 and PKC-delta, enhancing their kinase activities, leading to histone H2B phosphorylation. Dominant-negative PKC-delta (but not Mst1) blocks Acinus-initiated H2B phosphorylation. PKC-delta-deficient MEFs and siRNA-depleted PC12 cells abolish acinus-elicited H2B phosphorylation and chromatin condensation.","method":"Co-immunoprecipitation, dominant-negative constructs, siRNA knockdown, PKC-delta knockout MEFs, kinase activity assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal pulldown, genetic KO confirmation, and multiple cell models; two orthogonal approaches identify PKC-delta as downstream effector","pmids":["17721436"],"is_preprint":false},{"year":2007,"finding":"Akt phosphorylates zyxin on serine 142, leading to zyxin's association with Acinus-S in the nucleus and prevention of Acinus-S-triggered chromatin condensation. 14-3-3γ (but not ζ) selectively triggers zyxin nuclear translocation in an Akt-phosphorylation-dependent manner. The zyxin S142D phosphomimetic mutant diminishes Acinus proteolytic cleavage and chromatin condensation.","method":"Co-immunoprecipitation, site-directed mutagenesis, nuclear fractionation, apoptosis assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and mutagenesis, single lab, multiple orthogonal methods","pmids":["17572661"],"is_preprint":false},{"year":2008,"finding":"SRPK2 binds and phosphorylates Acinus, redistributing it from nuclear speckles to the nucleoplasm, resulting in cyclin A1 (but not A2) upregulation. Acinus S422D (SRPK2 phosphorylation mimetic) enhances cyclin A1 transcription; S422A blocks SRPK2's stimulatory effect. Ablation of Acinus or SRPK2 abrogates cyclin A1 expression and arrests leukemia cells at G1.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, siRNA knockdown, cell cycle analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct kinase assay, mutagenesis, and siRNA knockdown with defined cell cycle phenotype; multiple orthogonal methods","pmids":["18559500"],"is_preprint":false},{"year":2009,"finding":"AAC-11 physically interacts with Acinus via its leucine-zipper domain and protects Acinus from caspase-3 cleavage in vivo and in vitro, thereby preventing Acinus-mediated DNA fragmentation. A cell-permeable peptide mimicking the leucine-zipper subdomain of AAC-11 disrupts AAC-11–Acinus complex formation and potentiates drug-mediated apoptosis.","method":"Co-immunoprecipitation, in vitro caspase cleavage assay, siRNA knockdown, cell-permeable peptide competition","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vitro biochemical protection assay, and functional peptide competition; multiple orthogonal approaches","pmids":["19387494"],"is_preprint":false},{"year":2009,"finding":"Transcription corepressor CtBP2 directly binds Acinus, and this interaction is promoted by Akt-mediated phosphorylation of Acinus triggered by NGF/TrkA signaling. CtBP2 overexpression diminishes cyclin A1 transcription; CtBP2 depletion abolishes NGF's suppressive effect on cyclin A1 expression.","method":"Co-immunoprecipitation, siRNA knockdown, luciferase reporter assay, kinase assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, siRNA, and reporter assay; single lab with multiple methods","pmids":["19668232"],"is_preprint":false},{"year":2010,"finding":"Drosophila Acinus (dacn) is required for stabilization of early endosomes, modulating Notch and Egfr signaling levels. Loss of dacn also inhibits autophagosome maturation in response to starvation, while dacn overexpression causes lethality through enhanced autophagy independent of the Tor pathway.","method":"Loss-of-function genetic screen, genetic interaction, endosomal trafficking assays, autophagy assays","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotypes in Drosophila ortholog; single lab with multiple readouts","pmids":["20504956"],"is_preprint":false},{"year":2014,"finding":"In Drosophila, Acinus (Acn) stability and basal autophagy regulation depend on proteolytic cleavage by the caspase Dcp-1 and on AKT1-mediated phosphorylation. Flies expressing stabilized Acn forms (phosphomimetic S641,731D or caspase-resistant D527A) exhibit enhanced basal autophagy, increased starvation resistance, reduced Huntingtin-induced neurodegeneration, and prolonged lifespan.","method":"Caspase loss-of-function, site-directed mutagenesis, autophagy flux assays, in vivo neurodegeneration models, lifespan analysis","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic tools and in vivo functional readouts in Drosophila; single lab","pmids":["25332163"],"is_preprint":false},{"year":2015,"finding":"Acinus L is a direct substrate of mTORC1; it was identified by overlapping quantitative phosphoproteomics (upon raptor inhibition) with endogenous mTOR interactomics, and confirmed by co-immunoprecipitation and MS-enhanced kinase assays showing insulin- and amino-acid-responsive phosphorylation.","method":"Quantitative phosphoproteomics, co-immunoprecipitation, MS-enhanced in vitro kinase assay","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct kinase assay plus orthogonal proteomics; single lab","pmids":["25907765"],"is_preprint":false},{"year":2015,"finding":"Acinus functions in pre-mRNA splicing by enhancing inclusion of weak alternative cassette exons in a retinoic acid (RA)-dependent and -independent manner. The RRM domain is necessary for RA-dependent splicing activity, and RNPS1 represses the RA-independent splicing activity of Acinus. Acinus stimulates alternative 5' splice site usage of endogenous RARβ and Bcl-x transcripts.","method":"In vivo minigene splicing assays, domain deletion mutagenesis, endogenous pre-mRNA splicing assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigene assays with domain mutagenesis and endogenous target validation; single lab","pmids":["25205379"],"is_preprint":false},{"year":2016,"finding":"iCLIP mapping shows Acinus binds pre-mRNAs at a subset of suboptimal introns and also associates with spliced mRNAs, confirming its role as a peripheral EJC component. siRNA depletion of Acinus in HeLa cells preferentially disrupts inclusion of specific alternative cassette exons and faithful splicing of a subset of introns. Acinus directly regulates splicing of DFFA/ICAD transcript, a major DNA fragmentation regulator.","method":"iCLIP (cross-linking immunoprecipitation), siRNA depletion, RNA-seq","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide iCLIP binding map combined with siRNA-seq transcriptome; orthogonal methods confirm direct splicing role","pmids":["27365209"],"is_preprint":false},{"year":2017,"finding":"In Drosophila, Cdk5 phosphorylates Acinus at serine 437 to stabilize it and promote starvation-independent basal autophagy. Loss of Cdk5 or its cofactor p35 reduces pS437-Acn levels and basal autophagy. The phosphomimetic S437D mutation stabilizes Acn and promotes basal autophagy, and rescues neurodegeneration induced by polyQ proteins and Aβ42 (but not alpha-Synuclein).","method":"Genetic gain- and loss-of-function (Cdk5, p35 mutants), site-directed mutagenesis, autophagy assays, in vivo neurodegeneration models","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — Cdk5 gain/loss-of-function with phospho-specific antibody and phosphomimetic/phospho-dead mutant rescue; replicated in multiple neurodegeneration models","pmids":["29227247"],"is_preprint":false},{"year":2018,"finding":"The crystal structure of the human Acinus RRM domain was solved at 1.65 Å resolution, revealing a classical four-stranded antiparallel β-sheet with two flanking α-helices plus an additional C-terminal α-helix. The C-terminal helix partially occludes the ligand-binding surface of the β-sheet and harbors the caspase-3 target cleavage sequence, suggesting it shields RNA binding until proteolytic activation.","method":"X-ray crystallography","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure at 1.65 Å with structural interpretation, but functional validation of the C-terminal helix occlusion model is hypothesized rather than experimentally confirmed in this paper","pmids":["30042883"],"is_preprint":false},{"year":2014,"finding":"The sub-nuclear localization of Acinus isoforms differs: Acinus-S' colocalizes with SC35 in nuclear speckles (dependent on its C-terminal RS- and RD/E-rich region), while Acinus-L localizes diffusely in the nucleoplasm (dependent on its unique N-terminal SAP motif). The two isoforms influence each other's localization when co-expressed.","method":"Fluorescence microscopy, domain deletion/mutation constructs, co-localization with SC35 marker","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fluorescence localization with domain mapping via multiple deletion constructs; single lab","pmids":["25079509"],"is_preprint":false},{"year":2018,"finding":"Cdk5-mediated phosphorylation of Acn-S437 (Drosophila Acinus) is identified as a key regulator of basal autophagy, independent of metabolic stress. In nil1 (PPM-type phosphatase) loss-of-function animals, pS437-Acn levels are elevated, increasing neuronal autophagy and reducing polyQ accumulation in a Huntington's disease model.","method":"Genetic phosphatase screen, loss-of-function mutants, phospho-specific antibody, autophagy and neurodegeneration assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen plus loss-of-function confirmation with in vivo functional readout; single lab","pmids":["29782227"],"is_preprint":false},{"year":2019,"finding":"Recurrent ACIN1-NUTM1 gene fusions (joining exons 3 or 4 of ACIN1 to exon 3 of NUTM1) were identified in non-KMT2A-rearranged infant ALL by transcriptome analysis. The fusion transcripts contain the functional SAP (SAF-A/B, Acinus, and PIAS) DNA-binding domain of ACIN1 and most of NUTM1.","method":"Transcriptome sequencing (RNA-seq), RT-PCR confirmation, cytogenetic analysis","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — identification of recurrent fusion by RNA-seq with RT-PCR confirmation in two cases; no functional mechanistic follow-up of the fusion protein","pmids":["31515871"],"is_preprint":false},{"year":2019,"finding":"The RS (arginine/serine-rich) and RSB (RNPS1-SAP18-binding) domains of Acinus can modulate alternative splice site selection when tethered in an HIV-1 minigene reporter system, while full-length Acinus-S' does not affect splice site selection in this system.","method":"In vivo splicing assay with tethering constructs, minigene reporter","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (minigene tethering assay), with limited domain mapping","pmids":["31070279"],"is_preprint":false},{"year":2020,"finding":"Elevated SRSF3 promotes inclusion of MBNL1 exons 5 and 7 via CA-rich exonic elements, and an increase in the resulting MBNL18 isoform shifts Acin1 splicing from the Acin1-S to the Acin1-L isoform, leading to diminished DNA fragmentation under oxidative stress in colorectal cancer cells.","method":"Whole-transcriptome analysis, minigene splicing assay, siRNA knockdown, DNA fragmentation assay","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome plus functional splicing and DNA fragmentation assays; single lab","pmids":["33142236"],"is_preprint":false},{"year":2020,"finding":"Depletion of endogenous Acin1 isoforms activates brown adipogenic signatures in mouse C3H10T1/2 fibroblasts. Overexpression of Acin1-L versus Acin1-S exerts discriminative influences on brown adipogenesis through modulation of SRSF3 expression via an alternative splicing-coupled nonsense-mediated decay mechanism in a sequence-specific manner.","method":"siRNA knockdown, isoform overexpression, RNA-seq, splicing assays, brown adipogenesis differentiation assays","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq with functional differentiation assay and isoform-specific effects; single lab","pmids":["32629174"],"is_preprint":false},{"year":2022,"finding":"The PPM-type phosphatase Nil (CG6036) counterbalances Cdk5-dependent phosphorylation of Acinus-S437 in Drosophila neurons. Loss of Nil enhances pS437-Acn levels and elevates neuronal autophagy. Cd2+ exposure inhibits this PPM-type phosphatase, elevating acn-S437 phosphorylation, which is required for increased neuronal autophagy and protection against Cd2+-induced cytotoxicity.","method":"Genetic phosphatase screen, loss-of-function mutants, phospho-specific antibody, cadmium exposure, autophagy and viability assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen identification plus loss-of-function confirmation with chemical (Cd2+) validation; single lab","pmids":["35037620"],"is_preprint":false},{"year":2025,"finding":"Global deletion of Acin1 in mice causes embryonic lethality around E11.5, with developmental delays and increased apoptosis. Skeletal muscle myofiber-specific Acin1 knockout mice show enlarged myofibers, muscle damage, and regeneration. RNA-seq reveals that Acin1 deletion alters expression and splicing of genes crucial for muscle function, including splicing changes in genes associated with muscle disease and mitochondrial function, often producing immature or disease-associated splice variants.","method":"Conditional and global knockout mice, RNA-seq, immunohistochemistry, central nuclei counting","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean in vivo conditional KO with RNA-seq; single lab, single study","pmids":["40269054"],"is_preprint":false},{"year":2025,"finding":"A point mutation in SRRM2 associated with ALS disrupts the protein-protein interaction between SRRM2 and the splicing factor ACIN1, revealing ACIN1 as a binding partner of SRRM2 in the nuclear speckle/splicing machinery.","method":"Endogenous gene point mutation in cell line, protein-protein interaction assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single interaction loss demonstrated in a preprint; no direct mechanistic follow-up on ACIN1 itself","pmids":[],"is_preprint":true}],"current_model":"ACIN1 (Acinus) is a multifunctional nuclear RNA-binding protein that, upon caspase-3 cleavage, generates an active p17 fragment that induces apoptotic chromatin condensation and internucleosomal DNA fragmentation by activating PKC-delta and promoting H2B phosphorylation; this pro-apoptotic activity is antagonized by Akt-mediated phosphorylation at S422/S573 (which blocks caspase cleavage) and by binding partners such as AAC-11 and zyxin. In its non-apoptotic role, Acinus is a peripheral component of the exon junction complex (EJC) that directly binds pre-mRNA at suboptimal introns, regulates alternative splicing of numerous targets (including DFFA/ICAD, RARβ, and Bcl-x), and is a direct substrate of mTORC1 and SRPK2 (whose phosphorylation at S422 redistributes Acinus from nuclear speckles to nucleoplasm to upregulate cyclin A1); in Drosophila orthologs, Cdk5-dependent phosphorylation of the conserved serine 437 stabilizes Acinus and promotes starvation-independent basal autophagy that is critical for neuronal health."},"narrative":{"mechanistic_narrative":"ACIN1 (Acinus) is a dual-function nuclear protein that couples apoptotic chromatin dynamics to pre-mRNA splicing regulation [PMID:10490026, PMID:27365209]. It was first identified as a caspase-3 substrate whose proteolytic cleavage generates an active p17 fragment that drives apoptotic nuclear changes [PMID:10490026]; this activity is executed downstream by p17 binding to and activating PKC-delta, which promotes histone H2B phosphorylation, while ACIN1's principal apoptotic contribution is to internucleosomal DNA fragmentation rather than chromatin condensation per se [PMID:16537548, PMID:17721436]. The pro-apoptotic activity is gated by phosphorylation: Akt directly phosphorylates ACIN1 at serine 422 and serine 573 to render it resistant to caspase cleavage [PMID:16177823], and this state is reinforced by partner proteins AAC-11 and zyxin that bind ACIN1 and protect it from cleavage [PMID:17572661, PMID:19387494]. In its non-apoptotic role, ACIN1 is a peripheral exon junction complex component that binds pre-mRNA at suboptimal introns and regulates inclusion of weak alternative cassette exons, controlling splicing of targets including RARβ, Bcl-x, and the DNA-fragmentation regulator DFFA/ICAD [PMID:25205379, PMID:27365209]. Its activity is shaped by kinase input—SRPK2 phosphorylation at S422 redistributes ACIN1 from nuclear speckles to nucleoplasm to upregulate cyclin A1 and drive cell-cycle progression [PMID:18559500], and ACIN1 is a direct mTORC1 substrate [PMID:25907765]—and by isoform-specific subnuclear targeting governed by its RS/RD-rich and SAP domains [PMID:25079509]. In vivo, ACIN1 is essential for mouse embryonic development and for skeletal muscle homeostasis, where its loss alters splicing of muscle- and mitochondria-associated genes [PMID:40269054]. Recurrent ACIN1-NUTM1 fusions retaining the ACIN1 SAP DNA-binding domain occur in infant acute lymphoblastic leukemia [PMID:31515871].","teleology":[{"year":1999,"claim":"Established ACIN1 as a caspase-3-activated nuclear factor required for apoptotic nuclear morphology, defining its founding role in cell death.","evidence":"in vitro reconstitution with immunodepletion and antisense knockdown","pmids":["10490026"],"confidence":"High","gaps":["Did not define the downstream effectors of the cleaved fragment","Relationship between chromatin condensation and DNA fragmentation left unresolved"]},{"year":2005,"claim":"Showed that Akt phosphorylation at S422/S573 shields ACIN1 from caspase cleavage, identifying a survival-signaling brake on its pro-apoptotic activation.","evidence":"in vitro kinase assay, phosphomimetic/phospho-dead mutagenesis, siRNA in apoptosis assays","pmids":["16177823"],"confidence":"High","gaps":["Upstream signals controlling nuclear Akt activity not fully mapped","Did not address splicing functions of phosphorylated ACIN1"]},{"year":2006,"claim":"Reassigned ACIN1's apoptotic contribution from chromatin condensation to internucleosomal DNA fragmentation, refining the original 1999 model.","evidence":"inducible RNAi with intact-cell and cell-free apoptosis readouts","pmids":["16537548"],"confidence":"High","gaps":["Mechanism linking ACIN1 to the DNA fragmentation machinery not defined here","Isoform-specific contributions not dissected"]},{"year":2007,"claim":"Identified the effector pathway of the ACIN1 p17 fragment—activation of PKC-delta leading to H2B phosphorylation—connecting cleavage to histone modification.","evidence":"reciprocal Co-IP, dominant-negative constructs, PKC-delta knockout MEFs, kinase assays","pmids":["17721436"],"confidence":"High","gaps":["How H2B phosphorylation mechanically alters chromatin not resolved","Mst1 contribution remained ambiguous"]},{"year":2007,"claim":"Showed zyxin, recruited to the nucleus via Akt phosphorylation and 14-3-3γ, binds ACIN1-S and blocks its cleavage-dependent activity, adding a partner-mediated layer of apoptotic control.","evidence":"Co-IP, site-directed mutagenesis, nuclear fractionation, apoptosis assays","pmids":["17572661"],"confidence":"Medium","gaps":["Single-lab finding without independent replication","Structural basis of zyxin-ACIN1 binding unknown"]},{"year":2008,"claim":"Revealed a cell-cycle role: SRPK2 phosphorylation at S422 relocalizes ACIN1 from speckles to nucleoplasm to upregulate cyclin A1, linking ACIN1 phospho-state to transcription and proliferation.","evidence":"Co-IP, in vitro kinase assay, phosphomutants, siRNA, cell-cycle analysis","pmids":["18559500"],"confidence":"High","gaps":["Mechanism by which nucleoplasmic ACIN1 drives cyclin A1 transcription unclear","Whether speckle redistribution affects splicing not tested here"]},{"year":2009,"claim":"Identified AAC-11 as a leucine-zipper-dependent ACIN1 partner that protects against caspase cleavage, establishing a druggable anti-apoptotic interaction.","evidence":"Co-IP, in vitro caspase protection assay, siRNA, cell-permeable peptide competition","pmids":["19387494"],"confidence":"High","gaps":["Whether AAC-11 affects ACIN1 splicing function not examined","In vivo relevance of the peptide not established"]},{"year":2009,"claim":"Linked ACIN1 to transcriptional corepression via Akt-promoted CtBP2 binding downstream of NGF/TrkA, opposing cyclin A1 expression.","evidence":"Co-IP, siRNA, luciferase reporter, kinase assay","pmids":["19668232"],"confidence":"Medium","gaps":["Single-lab finding","Direct vs indirect effect on the cyclin A1 promoter not separated"]},{"year":2010,"claim":"Established a non-apoptotic role for the Drosophila ortholog in endosome stability and autophagosome maturation, broadening ACIN1 function into membrane trafficking and autophagy.","evidence":"loss-of-function genetic screen, genetic interactions, trafficking and autophagy assays in Drosophila","pmids":["20504956"],"confidence":"Medium","gaps":["Conservation of trafficking role in mammals untested","Molecular mechanism of endosome stabilization unknown"]},{"year":2014,"claim":"Defined isoform-specific subnuclear targeting of ACIN1, mapping speckle localization to the RS/RD-rich region and nucleoplasmic localization to the SAP-containing N-terminus.","evidence":"fluorescence microscopy with domain deletion constructs and SC35 co-localization","pmids":["25079509"],"confidence":"Medium","gaps":["Functional consequence of cross-isoform localization influence unclear","Single-lab finding"]},{"year":2014,"claim":"Demonstrated in Drosophila that caspase cleavage and Akt phosphorylation control Acinus stability to set basal autophagy, with stabilized forms conferring neuroprotection and longevity.","evidence":"caspase loss-of-function, phosphomimetic/cleavage-resistant mutants, autophagy flux, neurodegeneration and lifespan assays","pmids":["25332163"],"confidence":"Medium","gaps":["Mammalian relevance of the autophagy-stability axis untested","Molecular link from Acinus to autophagosome formation undefined"]},{"year":2015,"claim":"Established ACIN1 as a sequence-context splicing enhancer of weak cassette exons, with the RRM required for retinoic-acid-dependent activity and RNPS1 repressing RA-independent activity.","evidence":"minigene splicing assays, domain deletion mutagenesis, endogenous RARβ/Bcl-x readouts","pmids":["25205379"],"confidence":"Medium","gaps":["Genome-wide target scope not addressed here","Mechanism of RNPS1 repression unclear"]},{"year":2015,"claim":"Identified ACIN1-L as a direct, nutrient-responsive mTORC1 substrate, placing it under growth-signaling control.","evidence":"quantitative phosphoproteomics, mTOR interactomics, Co-IP, MS-enhanced kinase assay","pmids":["25907765"],"confidence":"Medium","gaps":["Functional consequence of mTORC1 phosphorylation on splicing or apoptosis not defined","Single-lab finding"]},{"year":2016,"claim":"Provided a genome-wide binding and functional map confirming ACIN1 as a peripheral EJC component that binds suboptimal introns and directly regulates splicing of DFFA/ICAD, unifying its splicing and apoptosis roles.","evidence":"iCLIP, siRNA depletion, RNA-seq in HeLa cells","pmids":["27365209"],"confidence":"High","gaps":["Causal link between ICAD splicing changes and apoptotic outcome not directly tested","Determinants of suboptimal-intron selectivity unresolved"]},{"year":2017,"claim":"Showed Cdk5/p35 phosphorylation of conserved S437 stabilizes Acinus and drives starvation-independent basal autophagy with selective neuroprotection in Drosophila.","evidence":"Cdk5/p35 gain- and loss-of-function, phospho-specific antibody, phosphomimetic rescue in neurodegeneration models","pmids":["29227247"],"confidence":"High","gaps":["Why protection is restricted to certain aggregating proteins not explained","Mammalian ACIN1 S437 equivalent not validated"]},{"year":2018,"claim":"Solved the human ACIN1 RRM crystal structure, revealing a C-terminal helix that occludes the RNA-binding surface and harbors the caspase-3 cleavage site, suggesting cleavage unmasks RNA binding.","evidence":"X-ray crystallography at 1.65 Å","pmids":["30042883"],"confidence":"Medium","gaps":["Occlusion model not functionally validated in the study","No structure of full-length or RNA-bound ACIN1"]},{"year":2018,"claim":"Identified the PPM-type phosphatase Nil as the counteracting enzyme controlling pS437-Acn levels, defining bidirectional phospho-regulation of autophagy.","evidence":"genetic phosphatase screen, loss-of-function mutants, phospho-specific antibody, autophagy/neurodegeneration assays","pmids":["29782227"],"confidence":"Medium","gaps":["Mammalian phosphatase counterpart unknown","Single-lab finding"]},{"year":2019,"claim":"Discovered recurrent ACIN1-NUTM1 fusions retaining the ACIN1 SAP domain in infant ALL, implicating ACIN1 in oncogenic rearrangement.","evidence":"transcriptome sequencing with RT-PCR confirmation and cytogenetics","pmids":["31515871"],"confidence":"Medium","gaps":["No functional characterization of the fusion protein","Mechanism of leukemogenesis untested"]},{"year":2019,"claim":"Mapped RS and RSB domains as modulators of splice-site selection in a tethered reporter, providing low-resolution domain dissection of ACIN1 splicing activity.","evidence":"tethered minigene reporter splicing assay","pmids":["31070279"],"confidence":"Low","gaps":["Single method, single lab without orthogonal validation","Full-length ACIN1-S' showed no effect, leaving physiological relevance unclear"]},{"year":2020,"claim":"Showed an SRSF3/MBNL1-driven splicing switch shifts Acin1 from the S to the L isoform to suppress DNA fragmentation under oxidative stress in cancer cells, tying isoform choice to apoptotic resistance.","evidence":"whole-transcriptome analysis, minigene assay, siRNA, DNA fragmentation assay","pmids":["33142236"],"confidence":"Medium","gaps":["Direct molecular basis of isoform-specific fragmentation difference unresolved","Single-lab finding"]},{"year":2020,"claim":"Demonstrated isoform-specific ACIN1 control of brown adipogenesis through SRSF3 splicing-coupled NMD, extending its splicing regulation to cell differentiation.","evidence":"siRNA, isoform overexpression, RNA-seq, differentiation assays in fibroblasts","pmids":["32629174"],"confidence":"Medium","gaps":["Relevance to in vivo adipose biology untested","Single-lab finding"]},{"year":2022,"claim":"Established that the Nil phosphatase counterbalances Cdk5 at Acn-S437 and that environmental Cd2+ tunes this axis to control neuronal autophagy and survival.","evidence":"genetic phosphatase screen, loss-of-function, phospho-specific antibody, cadmium exposure, autophagy/viability assays","pmids":["35037620"],"confidence":"Medium","gaps":["Mammalian conservation of the Cd2+-responsive axis untested","Direct phosphatase-substrate biochemistry not reconstituted"]},{"year":2025,"claim":"Showed ACIN1 is essential in vivo, with global knockout causing embryonic lethality and muscle-specific loss disrupting splicing of muscle and mitochondrial genes, establishing a developmental and tissue-homeostatic requirement.","evidence":"conditional and global knockout mice, RNA-seq, immunohistochemistry","pmids":["40269054"],"confidence":"Medium","gaps":["Causal mis-spliced targets driving the muscle phenotype not isolated","Embryonic lethality mechanism undefined"]},{"year":2025,"claim":"Implicated ACIN1 as an SRRM2 interaction partner in the nuclear speckle/splicing machinery, with an ALS-associated SRRM2 mutation disrupting the interaction.","evidence":"endogenous point-mutation cell line and protein-protein interaction assay (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint without peer review and no mechanistic follow-up on ACIN1","Functional consequence for ACIN1 splicing activity unknown"]},{"year":null,"claim":"How the apoptotic, splicing, cell-cycle, and autophagy functions of ACIN1 are integrated in a single mammalian cell—and which mis-spliced targets mediate its developmental essentiality—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking phospho-state, isoform, and localization to specific cellular outcomes","Mammalian autophagy role of ACIN1 not directly demonstrated","Functional consequences of the ACIN1-NUTM1 fusion uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[11,12,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,7]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,15]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[5,15]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8,9,13]}],"complexes":["exon junction complex (EJC)","ASAP/PSAP complex (with RNPS1, SAP18)"],"partners":["PRKCD","AKT1","SRPK2","AAC-11","ZYX","CTBP2","RNPS1","SRRM2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKV3","full_name":"Apoptotic chromatin condensation inducer in the nucleus","aliases":[],"length_aa":1341,"mass_kda":151.9,"function":"Auxiliary component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junction on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. Component of the ASAP complexes which bind RNA in a sequence-independent manner and are proposed to be recruited to the EJC prior to or during the splicing process and to regulate specific excision of introns in specific transcription subsets; ACIN1 confers RNA-binding to the complex. The ASAP complex can inhibit RNA processing during in vitro splicing reactions. The ASAP complex promotes apoptosis and is disassembled after induction of apoptosis. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the activity is different from the established EJC assembly and function. Induces apoptotic chromatin condensation after activation by CASP3. Regulates cyclin A1, but not cyclin A2, expression in leukemia cells","subcellular_location":"Nucleus; Nucleus speckle; Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UKV3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ACIN1","classification":"Common Essential","n_dependent_lines":1054,"n_total_lines":1208,"dependency_fraction":0.8725165562913907},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TOP1","stoichiometry":4.0},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"PRPF4B","stoichiometry":0.2},{"gene":"RBM14","stoichiometry":0.2},{"gene":"RBM33","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ACIN1","total_profiled":1310},"omim":[{"mim_id":"618599","title":"CADHERIN 24; CDH24","url":"https://www.omim.org/entry/618599"},{"mim_id":"604562","title":"APOPTOTIC CHROMATIN CONDENSATION INDUCER 1; ACIN1","url":"https://www.omim.org/entry/604562"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ACIN1"},"hgnc":{"alias_symbol":["KIAA0670","fSAP152"],"prev_symbol":["ACINUS"]},"alphafold":{"accession":"Q9UKV3","domains":[{"cath_id":"-","chopping":"76-107","consensus_level":"medium","plddt":92.7831,"start":76,"end":107},{"cath_id":"3.30.70.330","chopping":"1014-1097","consensus_level":"high","plddt":88.1829,"start":1014,"end":1097},{"cath_id":"1.20.5","chopping":"1227-1318","consensus_level":"medium","plddt":86.3027,"start":1227,"end":1318}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKV3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKV3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKV3-F1-predicted_aligned_error_v6.png","plddt_mean":50.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACIN1","jax_strain_url":"https://www.jax.org/strain/search?query=ACIN1"},"sequence":{"accession":"Q9UKV3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKV3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKV3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKV3"}},"corpus_meta":[{"pmid":"10490026","id":"PMC_10490026","title":"Acinus is a caspase-3-activated protein required for apoptotic chromatin condensation.","date":"1999","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10490026","citation_count":362,"is_preprint":false},{"pmid":"23558573","id":"PMC_23558573","title":"SOX10 is a novel marker of acinus and intercalated duct differentiation in salivary gland tumors: a clue to the histogenesis for tumor diagnosis.","date":"2013","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/23558573","citation_count":138,"is_preprint":false},{"pmid":"8349710","id":"PMC_8349710","title":"Use of transgenic mice to map cis-acting elements in the liver fatty acid-binding protein gene (Fabpl) that regulate its cell lineage-specific, differentiation-dependent, and spatial patterns of expression in the gut epithelium and in the liver acinus.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8349710","citation_count":112,"is_preprint":false},{"pmid":"2472341","id":"PMC_2472341","title":"Hepatic enzymic zonation: a reevaluation of the concept of the liver acinus.","date":"1989","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/2472341","citation_count":110,"is_preprint":false},{"pmid":"30063238","id":"PMC_30063238","title":"A glass-based, continuously zonated and vascularized human liver acinus microphysiological system (vLAMPS) designed for experimental modeling of diseases and ADME/TOX.","date":"2018","source":"Lab on a chip","url":"https://pubmed.ncbi.nlm.nih.gov/30063238","citation_count":108,"is_preprint":false},{"pmid":"3673919","id":"PMC_3673919","title":"Pulmonary acinus: geometry and morphometry of the peripheral airway system in rat and rabbit.","date":"1987","source":"The American journal of anatomy","url":"https://pubmed.ncbi.nlm.nih.gov/3673919","citation_count":96,"is_preprint":false},{"pmid":"2898495","id":"PMC_2898495","title":"Complementary distribution of carbamoylphosphate synthetase (ammonia) and glutamine synthetase in rat liver acinus is regulated at a pretranslational level.","date":"1988","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/2898495","citation_count":95,"is_preprint":false},{"pmid":"1332499","id":"PMC_1332499","title":"Connexins and glucagon receptors during development of rat hepatic acinus.","date":"1992","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/1332499","citation_count":84,"is_preprint":false},{"pmid":"16177823","id":"PMC_16177823","title":"Akt phosphorylates acinus and inhibits its proteolytic cleavage, preventing chromatin condensation.","date":"2005","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16177823","citation_count":78,"is_preprint":false},{"pmid":"1542056","id":"PMC_1542056","title":"Metabolic heterogeneity of hepatocytes across the liver acinus.","date":"1992","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/1542056","citation_count":78,"is_preprint":false},{"pmid":"18559500","id":"PMC_18559500","title":"Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating acinus and regulating cyclin A1.","date":"2008","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18559500","citation_count":75,"is_preprint":false},{"pmid":"19387494","id":"PMC_19387494","title":"The antiapoptotic protein AAC-11 interacts with and regulates Acinus-mediated DNA fragmentation.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19387494","citation_count":64,"is_preprint":false},{"pmid":"7076132","id":"PMC_7076132","title":"Reciprocal distribution of hexokinase and glucokinase in the periportal and perivenous zone of the rat liver acinus.","date":"1982","source":"Hoppe-Seyler's Zeitschrift fur physiologische Chemie","url":"https://pubmed.ncbi.nlm.nih.gov/7076132","citation_count":61,"is_preprint":false},{"pmid":"7198303","id":"PMC_7198303","title":"Salivary gland of the tick vector (R. appendiculatus) of East Coast fever. I. Ultrastructure of the type III acinus.","date":"1981","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/7198303","citation_count":49,"is_preprint":false},{"pmid":"3019862","id":"PMC_3019862","title":"The isolation of functionally heterogeneous hepatocytes of the proximal and distal half of the liver acinus in the rat.","date":"1986","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/3019862","citation_count":45,"is_preprint":false},{"pmid":"16537548","id":"PMC_16537548","title":"Loss of Acinus inhibits oligonucleosomal DNA fragmentation but not chromatin condensation during apoptosis.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16537548","citation_count":44,"is_preprint":false},{"pmid":"6859265","id":"PMC_6859265","title":"Functional and anatomic heterogeneity in the liver acinus: impact on transport.","date":"1983","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/6859265","citation_count":44,"is_preprint":false},{"pmid":"3548484","id":"PMC_3548484","title":"Development of the pulmonary acinus in fetal rat lung: a study based on an antiserum recognizing surfactant-associated proteins.","date":"1987","source":"Anatomy and embryology","url":"https://pubmed.ncbi.nlm.nih.gov/3548484","citation_count":41,"is_preprint":false},{"pmid":"7198304","id":"PMC_7198304","title":"Salivary gland of the tick vector (R. appendiculatus) of East Coast fever. II. Cellular basis for fluid secretion in the type III acinus.","date":"1981","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/7198304","citation_count":41,"is_preprint":false},{"pmid":"17572661","id":"PMC_17572661","title":"Akt phosphorylation of zyxin mediates its interaction with acinus-S and prevents acinus-triggered chromatin condensation.","date":"2007","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/17572661","citation_count":40,"is_preprint":false},{"pmid":"27365209","id":"PMC_27365209","title":"The RNA-binding profile of Acinus, a peripheral component of the exon junction complex, reveals its role in splicing regulation.","date":"2016","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/27365209","citation_count":38,"is_preprint":false},{"pmid":"8078390","id":"PMC_8078390","title":"Endothelial cell heterogeneity in the normal human liver acinus: in situ immunohistochemical demonstration.","date":"1994","source":"Liver","url":"https://pubmed.ncbi.nlm.nih.gov/8078390","citation_count":38,"is_preprint":false},{"pmid":"10846044","id":"PMC_10846044","title":"A three-dimensional model of the human pulmonary acinus.","date":"2000","source":"Journal of applied physiology (Bethesda, Md. : 1985)","url":"https://pubmed.ncbi.nlm.nih.gov/10846044","citation_count":35,"is_preprint":false},{"pmid":"33307106","id":"PMC_33307106","title":"Analysis of reproducibility and robustness of a human microfluidic four-cell liver acinus microphysiology system (LAMPS).","date":"2020","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/33307106","citation_count":34,"is_preprint":false},{"pmid":"29227247","id":"PMC_29227247","title":"Stress-induced Cdk5 activity enhances cytoprotective basal autophagy in Drosophila melanogaster by phosphorylating acinus at serine437.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29227247","citation_count":32,"is_preprint":false},{"pmid":"7882903","id":"PMC_7882903","title":"Alveolar epithelial composition and architecture of the late fetal pulmonary acinus: an immunocytochemical and morphometric study in a rat model of pulmonary hypoplasia and congenital diaphragmatic hernia.","date":"1994","source":"Experimental lung research","url":"https://pubmed.ncbi.nlm.nih.gov/7882903","citation_count":30,"is_preprint":false},{"pmid":"2470762","id":"PMC_2470762","title":"Induction of P-450IIB genes within the rat liver acinus is not dependent on the chemical inducer or on the acinar organization.","date":"1989","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2470762","citation_count":30,"is_preprint":false},{"pmid":"11374055","id":"PMC_11374055","title":"Maxi K+ channels co-localised with CFTR in the apical membrane of an exocrine gland acinus: possible involvement in secretion.","date":"2001","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11374055","citation_count":30,"is_preprint":false},{"pmid":"31515871","id":"PMC_31515871","title":"Cryptic recurrent ACIN1-NUTM1 fusions in non-KMT2A-rearranged infant acute lymphoblastic leukemia.","date":"2019","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31515871","citation_count":29,"is_preprint":false},{"pmid":"2592252","id":"PMC_2592252","title":"In situ kinetic parameters of glucose-6-phosphate dehydrogenase and phosphogluconate dehydrogenase in different areas of the rat liver acinus.","date":"1989","source":"The Histochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/2592252","citation_count":29,"is_preprint":false},{"pmid":"20844151","id":"PMC_20844151","title":"PKCzeta regulates cell polarisation and proliferation restriction during mammary acinus formation.","date":"2010","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/20844151","citation_count":28,"is_preprint":false},{"pmid":"31402305","id":"PMC_31402305","title":"Mechanical Stabilization of the Glandular Acinus by Linker of Nucleoskeleton and Cytoskeleton Complex.","date":"2019","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/31402305","citation_count":28,"is_preprint":false},{"pmid":"8898649","id":"PMC_8898649","title":"The location of hepatocytes in the rat liver acinus determines their sensitivity to calcium-mobilizing hormones.","date":"1996","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/8898649","citation_count":28,"is_preprint":false},{"pmid":"15783623","id":"PMC_15783623","title":"Diffusion-reaction in branched structures: theory and application to the lung acinus.","date":"2005","source":"Physical review letters","url":"https://pubmed.ncbi.nlm.nih.gov/15783623","citation_count":27,"is_preprint":false},{"pmid":"20504956","id":"PMC_20504956","title":"Drosophila acinus encodes a novel regulator of endocytic and autophagic trafficking.","date":"2010","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20504956","citation_count":26,"is_preprint":false},{"pmid":"3758946","id":"PMC_3758946","title":"Heterogeneous expression of phenobarbital-inducible cytochrome P-450 genes within the hepatic acinus in the rat.","date":"1986","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/3758946","citation_count":26,"is_preprint":false},{"pmid":"8286785","id":"PMC_8286785","title":"Ultrastructural features of alveolar epithelial cells in the late fetal pulmonary acinus: a comparison between normal and hypoplastic lungs using a rat model of pulmonary hypoplasia and congenital diaphragmatic hernia.","date":"1993","source":"Microscopy research and technique","url":"https://pubmed.ncbi.nlm.nih.gov/8286785","citation_count":26,"is_preprint":false},{"pmid":"15762849","id":"PMC_15762849","title":"Ultrastructural zonal heterogeneity of hepatocytes and mitochondria within the hepatic acinus during liver regeneration after partial hepatectomy.","date":"2005","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15762849","citation_count":26,"is_preprint":false},{"pmid":"10403118","id":"PMC_10403118","title":"Distribution of alcohol dehydrogenase isoenzymes in the human liver acinus.","date":"1999","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10403118","citation_count":24,"is_preprint":false},{"pmid":"17721436","id":"PMC_17721436","title":"Acinus-provoked protein kinase C delta isoform activation is essential for apoptotic chromatin condensation.","date":"2007","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/17721436","citation_count":23,"is_preprint":false},{"pmid":"19668232","id":"PMC_19668232","title":"NGF inhibits human leukemia proliferation by downregulating cyclin A1 expression through promoting acinus/CtBP2 association.","date":"2009","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19668232","citation_count":22,"is_preprint":false},{"pmid":"23563756","id":"PMC_23563756","title":"A microfluidic device mimicking acinar concentration gradients across the liver acinus.","date":"2013","source":"Biomedical microdevices","url":"https://pubmed.ncbi.nlm.nih.gov/23563756","citation_count":22,"is_preprint":false},{"pmid":"3562346","id":"PMC_3562346","title":"Primary culture of epithelial cells derived from the rat ventral prostate: formation of three-dimensional acinus-like structure in collagen gel.","date":"1987","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/3562346","citation_count":22,"is_preprint":false},{"pmid":"25878108","id":"PMC_25878108","title":"Epstein-Barr virus latent membrane protein 2 induces autophagy to promote abnormal acinus formation.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/25878108","citation_count":21,"is_preprint":false},{"pmid":"35884248","id":"PMC_35884248","title":"Liver Acinus Dynamic Chip for Assessment of Drug-Induced Zonal Hepatotoxicity.","date":"2022","source":"Biosensors","url":"https://pubmed.ncbi.nlm.nih.gov/35884248","citation_count":19,"is_preprint":false},{"pmid":"30272666","id":"PMC_30272666","title":"Measuring Hypopharyngeal Gland Acinus Size in Honey Bee (Apis mellifera) Workers.","date":"2018","source":"Journal of visualized experiments : JoVE","url":"https://pubmed.ncbi.nlm.nih.gov/30272666","citation_count":19,"is_preprint":false},{"pmid":"25332163","id":"PMC_25332163","title":"Acinus integrates AKT1 and subapoptotic caspase activities to regulate basal autophagy.","date":"2014","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25332163","citation_count":18,"is_preprint":false},{"pmid":"25907765","id":"PMC_25907765","title":"Functional Proteomics Identifies Acinus L as a Direct Insulin- and Amino Acid-Dependent Mammalian Target of Rapamycin Complex 1 (mTORC1) Substrate.","date":"2015","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/25907765","citation_count":18,"is_preprint":false},{"pmid":"9493134","id":"PMC_9493134","title":"Transient swelling of salivary acinus induced by acetylcholine stimulation: water secretion pathway in rat submandibular gland.","date":"1998","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/9493134","citation_count":18,"is_preprint":false},{"pmid":"23205493","id":"PMC_23205493","title":"Chronic low-dose radiation inhibits the cells death by cytotoxic high-dose radiation increasing the level of AKT and acinus proteins via NF-κB activation.","date":"2013","source":"International journal of radiation biology","url":"https://pubmed.ncbi.nlm.nih.gov/23205493","citation_count":17,"is_preprint":false},{"pmid":"9072537","id":"PMC_9072537","title":"Reconstruction of prostatic acinus-like structure from ventral and dorsolateral prostatic epithelial cells of the rat in three-dimensional collagen gel matrix culture.","date":"1997","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/9072537","citation_count":17,"is_preprint":false},{"pmid":"25205379","id":"PMC_25205379","title":"Role of Acinus in regulating retinoic acid-responsive gene pre-mRNA splicing.","date":"2015","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25205379","citation_count":16,"is_preprint":false},{"pmid":"23404906","id":"PMC_23404906","title":"Increased extracellular matrix density decreases MCF10A breast cell acinus formation in 3D culture conditions.","date":"2013","source":"Journal of tissue engineering and regenerative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23404906","citation_count":16,"is_preprint":false},{"pmid":"22258315","id":"PMC_22258315","title":"Efficiency of primary saliva secretion: an analysis of parameter dependence in dynamic single-cell and acinus models, with application to aquaporin knockout studies.","date":"2012","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/22258315","citation_count":16,"is_preprint":false},{"pmid":"17409846","id":"PMC_17409846","title":"The ACIN1 gene is hypermethylated in early stage lung adenocarcinoma.","date":"2006","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/17409846","citation_count":14,"is_preprint":false},{"pmid":"30201066","id":"PMC_30201066","title":"[Expression and Significance of ACIN1 mRNA in Platelets of Lung Cancer].","date":"2018","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30201066","citation_count":14,"is_preprint":false},{"pmid":"37303831","id":"PMC_37303831","title":"Microneedle array facilitates hepatic sinusoid construction in a large-scale liver-acinus-chip microsystem.","date":"2023","source":"Microsystems & nanoengineering","url":"https://pubmed.ncbi.nlm.nih.gov/37303831","citation_count":14,"is_preprint":false},{"pmid":"9548666","id":"PMC_9548666","title":"Ca2+ signaling in the pancreatic acinus.","date":"1998","source":"Pancreas","url":"https://pubmed.ncbi.nlm.nih.gov/9548666","citation_count":13,"is_preprint":false},{"pmid":"16639616","id":"PMC_16639616","title":"Small Rho GTPases are important for acinus formation in a human salivary gland cell line.","date":"2006","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/16639616","citation_count":13,"is_preprint":false},{"pmid":"6542909","id":"PMC_6542909","title":"Microbiochemical investigation on diurnal rhythmic changes of the activities of the lactate dehydrogenase in the periportal and perivenous zones of the acinus of the rat liver.","date":"1984","source":"Histochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6542909","citation_count":13,"is_preprint":false},{"pmid":"33142236","id":"PMC_33142236","title":"The SRSF3-MBNL1-Acin1 circuit constitutes an emerging axis to lessen DNA fragmentation in colorectal cancer via an alternative splicing mechanism.","date":"2020","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/33142236","citation_count":12,"is_preprint":false},{"pmid":"943970","id":"PMC_943970","title":"DNA synthesis and cell proliferation in the simple liver acinus of 10 to 20-day-old rats: evidence for cell fusion.","date":"1976","source":"The Anatomical record","url":"https://pubmed.ncbi.nlm.nih.gov/943970","citation_count":12,"is_preprint":false},{"pmid":"32629174","id":"PMC_32629174","title":"Altered expressions and splicing profiles of Acin1 transcripts differentially modulate brown adipogenesis through an alternative splicing mechanism.","date":"2020","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/32629174","citation_count":11,"is_preprint":false},{"pmid":"29782227","id":"PMC_29782227","title":"Cdk5-mediated Acn/Acinus phosphorylation regulates basal autophagy independently of metabolic stress.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/29782227","citation_count":11,"is_preprint":false},{"pmid":"19195057","id":"PMC_19195057","title":"Cell-permeable Tat-NBD peptide attenuates rat pancreatitis and acinus cell inflammation response.","date":"2009","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/19195057","citation_count":10,"is_preprint":false},{"pmid":"22161830","id":"PMC_22161830","title":"c-Jun N-terminal kinase activity supports multiple phases of 3D-mammary epithelial acinus formation.","date":"2011","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/22161830","citation_count":10,"is_preprint":false},{"pmid":"34581719","id":"PMC_34581719","title":"Engineering of a functional pancreatic acinus with reprogrammed cancer cells by induced PTF1a expression.","date":"2021","source":"Lab on a chip","url":"https://pubmed.ncbi.nlm.nih.gov/34581719","citation_count":9,"is_preprint":false},{"pmid":"25079509","id":"PMC_25079509","title":"The SAP motif and C-terminal RS- and RD/E-rich region influences the sub-nuclear localization of Acinus isoforms.","date":"2014","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25079509","citation_count":9,"is_preprint":false},{"pmid":"24109232","id":"PMC_24109232","title":"Epstein-Barr virus latent membrane protein 2 effects on epithelial acinus development reveal distinct requirements for the PY and YEEA motifs.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/24109232","citation_count":9,"is_preprint":false},{"pmid":"6854007","id":"PMC_6854007","title":"Differential filipin labeling of the luminal membranes lining the pancreatic acinus.","date":"1983","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/6854007","citation_count":9,"is_preprint":false},{"pmid":"19058849","id":"PMC_19058849","title":"A novel role for acinus and MCM2 as host-specific signaling enhancers of DNA-damage-induced apoptosis in association with viral protein gp70.","date":"2008","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/19058849","citation_count":8,"is_preprint":false},{"pmid":"2385154","id":"PMC_2385154","title":"Streaming liver. VII: DNA turnover in acinus zone-3.","date":"1990","source":"Liver","url":"https://pubmed.ncbi.nlm.nih.gov/2385154","citation_count":8,"is_preprint":false},{"pmid":"34543702","id":"PMC_34543702","title":"Prediction of hepatic drug clearance with a human microfluidic four-cell liver acinus microphysiology system.","date":"2021","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/34543702","citation_count":7,"is_preprint":false},{"pmid":"31070279","id":"PMC_31070279","title":"The arginine and serine-rich domains of Acinus modulate splicing.","date":"2019","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/31070279","citation_count":6,"is_preprint":false},{"pmid":"34312803","id":"PMC_34312803","title":"Inhibition of cell proliferation and promotion of acinus-like structure formation from goat mammary epithelial cells via Wnt/β-catenin signaling.","date":"2021","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/34312803","citation_count":6,"is_preprint":false},{"pmid":"32664285","id":"PMC_32664285","title":"Efficient Therapeutic Delivery by a Novel Cell-Penetrating Peptide Derived from Acinus.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32664285","citation_count":6,"is_preprint":false},{"pmid":"1833303","id":"PMC_1833303","title":"Homogeneous distribution of phosphofructokinase in the rat liver acinus: a quantitative histochemical study.","date":"1991","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/1833303","citation_count":6,"is_preprint":false},{"pmid":"18538524","id":"PMC_18538524","title":"Gas diffusion in a pulmonary acinus model: experiments with hyperpolarized helium-3.","date":"2008","source":"Magnetic resonance imaging","url":"https://pubmed.ncbi.nlm.nih.gov/18538524","citation_count":6,"is_preprint":false},{"pmid":"16767516","id":"PMC_16767516","title":"AMPA-induced excitotoxicity increases nuclear levels of CAD, endonuclease G, and acinus and induces chromatin condensation in rat hippocampal pyramidal neurons.","date":"2006","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/16767516","citation_count":4,"is_preprint":false},{"pmid":"17517822","id":"PMC_17517822","title":"Spatial distribution of CYP2B1/2 messenger RNA within the rat liver acinus following exposure to the inducers phenobarbital and dieldrin.","date":"2007","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/17517822","citation_count":4,"is_preprint":false},{"pmid":"30042883","id":"PMC_30042883","title":"Crystal structure of human Acinus RNA recognition motif domain.","date":"2018","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/30042883","citation_count":3,"is_preprint":false},{"pmid":"40269054","id":"PMC_40269054","title":"The splicing factor Acin1 is essential for embryonic development but has limited effects on muscle structure and homeostasis.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40269054","citation_count":3,"is_preprint":false},{"pmid":"7619334","id":"PMC_7619334","title":"Consequences of prolonged inhalation of ozone on F344/N rats: collaborative studies. Part IX: Changes in the tracheobronchial epithelium, pulmonary acinus, and lung antioxidant enzyme activity.","date":"1995","source":"Research report (Health Effects Institute)","url":"https://pubmed.ncbi.nlm.nih.gov/7619334","citation_count":3,"is_preprint":false},{"pmid":"9697229","id":"PMC_9697229","title":"Consequences of prolonged inhalation of ozone on F344/N rats: collaborative studies. Part XIII. A comparison of changes in the tracheobronchial epithelium and pulmonary acinus in male rats at 3 and 20 months.","date":"1998","source":"Research report (Health Effects Institute)","url":"https://pubmed.ncbi.nlm.nih.gov/9697229","citation_count":3,"is_preprint":false},{"pmid":"35037620","id":"PMC_35037620","title":"A phosphoswitch at acinus-serine437 controls autophagic responses to cadmium exposure and neurodegenerative stress.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/35037620","citation_count":2,"is_preprint":false},{"pmid":"30661732","id":"PMC_30661732","title":"Three-dimensional collective cell motions in an acinus-like lumen.","date":"2019","source":"Journal of biomechanics","url":"https://pubmed.ncbi.nlm.nih.gov/30661732","citation_count":2,"is_preprint":false},{"pmid":"12164086","id":"PMC_12164086","title":"PCNA expression and electron microscopic study of acinus-forming hepatocytes in chronic hepatitis B.","date":"2002","source":"The Korean journal of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12164086","citation_count":2,"is_preprint":false},{"pmid":"27796954","id":"PMC_27796954","title":"Using 3D Culture of Primary Mammary Epithelial Cells to Define Molecular Entities Required for Acinus Formation: Analyzing MAP Kinase Phosphatases.","date":"2017","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/27796954","citation_count":2,"is_preprint":false},{"pmid":"7689795","id":"PMC_7689795","title":"Occurrence of a third type of secretory cell in the acinus of the rat submandibular gland.","date":"1993","source":"The Anatomical record","url":"https://pubmed.ncbi.nlm.nih.gov/7689795","citation_count":2,"is_preprint":false},{"pmid":"35367411","id":"PMC_35367411","title":"Mathematical modeling of pulmonary acinus structure: Verification of acinar shape effects on pathway structure using rat lungs.","date":"2022","source":"Respiratory physiology & neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35367411","citation_count":1,"is_preprint":false},{"pmid":"15902964","id":"PMC_15902964","title":"Temporal reduction in size of salivary acinus in rats induced by theophylline.","date":"2005","source":"Toxicologic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15902964","citation_count":1,"is_preprint":false},{"pmid":"27308482","id":"PMC_27308482","title":"Activated Acinus boosts basal autophagy.","date":"2015","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27308482","citation_count":0,"is_preprint":false},{"pmid":"42063103","id":"PMC_42063103","title":"Recapitulation of clinical and molecular hallmarks of lipid-induced hepatic insulin resistance in a zonated, vascularized human liver acinus microphysiological system during metabolic dysfunction-associated steatotic liver disease (MASLD) progression.","date":"2026","source":"BMC biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/42063103","citation_count":0,"is_preprint":false},{"pmid":"12561331","id":"PMC_12561331","title":"[Detection of hepatoid glands and distinctive features of hepatoid acinus].","date":"2002","source":"Izvestiia Akademii nauk. Seriia biologicheskaia","url":"https://pubmed.ncbi.nlm.nih.gov/12561331","citation_count":0,"is_preprint":false},{"pmid":"21604497","id":"PMC_21604497","title":"[The expression of X-linked inhibitor of apoptosis protein and cell apoptosis in caerulein-stimulated rat pancreatic acinus AR42J cell lines].","date":"2011","source":"Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/21604497","citation_count":0,"is_preprint":false},{"pmid":"42255464","id":"PMC_42255464","title":"Scaling human liver microphysiological systems: implementing a higher-throughput liver acinus microphysiological system platform.","date":"2026","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/42255464","citation_count":0,"is_preprint":false},{"pmid":"41279985","id":"PMC_41279985","title":"Recapitulation of clinical and molecular hallmarks of lipid-induced hepatic insulin resistance in a zonated, vascularized human liver acinus microphysiological system during metabolic dysfunction-associated steatotic liver disease (MASLD) progression.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41279985","citation_count":0,"is_preprint":false},{"pmid":"3798013","id":"PMC_3798013","title":"Microcorrosion casting of the human respiratory acinus.","date":"1986","source":"Scanning electron microscopy","url":"https://pubmed.ncbi.nlm.nih.gov/3798013","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.11.675713","title":"A point mutation in the nuclear speckle protein and splicing factor SRRM2 is associated with amyotrophic lateral sclerosis and causes dysregulation of synapse-associated genes","date":"2025-09-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.11.675713","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.12.642916","title":"ADAR1 regulates alternative splicing through an RNA editing-independent mechanism","date":"2025-03-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.12.642916","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47785,"output_tokens":6071,"usd":0.11721,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14784,"output_tokens":6468,"usd":0.11781,"stage2_stop_reason":"end_turn"},"total_usd":0.23502,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Acinus (ACIN1) is a nuclear factor that induces apoptotic chromatin condensation after proteolytic cleavage by caspase-3, without inducing DNA fragmentation. Immunodepletion experiments showed Acinus is essential for apoptotic chromatin condensation in vitro.\",\n      \"method\": \"In vitro reconstitution system, immunodepletion, antisense knockdown\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with immunodepletion and antisense confirmation; foundational study replicated by multiple subsequent labs\",\n      \"pmids\": [\"10490026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Akt directly phosphorylates Acinus on serine 422 and serine 573, making Acinus resistant to caspase cleavage in the nucleus and inhibiting Acinus-dependent chromatin condensation. Phosphomimetic mutant (S422,573D) resists apoptotic cleavage; unphosphorylatable mutant accelerates chromatin condensation. Nuclear Akt depletion provokes apoptotic cleavage of Acinus.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, siRNA knockdown, cell-based apoptosis assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct kinase assay with mutagenesis plus cell-based validation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"16177823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Knockdown of Acinus isoforms by inducible RNAi does not inhibit apoptotic chromatin condensation but does reduce oligonucleosomal DNA fragmentation, indicating Acinus contributes to internucleosomal DNA cleavage rather than chromatin condensation during apoptosis. Acinus is not required for nuclear localization of ASAP complex subunits SAP18 and RNPS1.\",\n      \"method\": \"Inducible RNAi stable knockdown, cell-free apoptosis system, DNA fragmentation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean inducible RNAi with both intact-cell and cell-free system readouts; contradicts original chromatin condensation claim with rigorous controls\",\n      \"pmids\": [\"16537548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The caspase-cleaved active Acinus p17 fragment promotes apoptotic chromatin condensation by binding to both Mst1 and PKC-delta, enhancing their kinase activities, leading to histone H2B phosphorylation. Dominant-negative PKC-delta (but not Mst1) blocks Acinus-initiated H2B phosphorylation. PKC-delta-deficient MEFs and siRNA-depleted PC12 cells abolish acinus-elicited H2B phosphorylation and chromatin condensation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative constructs, siRNA knockdown, PKC-delta knockout MEFs, kinase activity assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal pulldown, genetic KO confirmation, and multiple cell models; two orthogonal approaches identify PKC-delta as downstream effector\",\n      \"pmids\": [\"17721436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Akt phosphorylates zyxin on serine 142, leading to zyxin's association with Acinus-S in the nucleus and prevention of Acinus-S-triggered chromatin condensation. 14-3-3γ (but not ζ) selectively triggers zyxin nuclear translocation in an Akt-phosphorylation-dependent manner. The zyxin S142D phosphomimetic mutant diminishes Acinus proteolytic cleavage and chromatin condensation.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, nuclear fractionation, apoptosis assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and mutagenesis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17572661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SRPK2 binds and phosphorylates Acinus, redistributing it from nuclear speckles to the nucleoplasm, resulting in cyclin A1 (but not A2) upregulation. Acinus S422D (SRPK2 phosphorylation mimetic) enhances cyclin A1 transcription; S422A blocks SRPK2's stimulatory effect. Ablation of Acinus or SRPK2 abrogates cyclin A1 expression and arrests leukemia cells at G1.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, siRNA knockdown, cell cycle analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct kinase assay, mutagenesis, and siRNA knockdown with defined cell cycle phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"18559500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"AAC-11 physically interacts with Acinus via its leucine-zipper domain and protects Acinus from caspase-3 cleavage in vivo and in vitro, thereby preventing Acinus-mediated DNA fragmentation. A cell-permeable peptide mimicking the leucine-zipper subdomain of AAC-11 disrupts AAC-11–Acinus complex formation and potentiates drug-mediated apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro caspase cleavage assay, siRNA knockdown, cell-permeable peptide competition\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vitro biochemical protection assay, and functional peptide competition; multiple orthogonal approaches\",\n      \"pmids\": [\"19387494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Transcription corepressor CtBP2 directly binds Acinus, and this interaction is promoted by Akt-mediated phosphorylation of Acinus triggered by NGF/TrkA signaling. CtBP2 overexpression diminishes cyclin A1 transcription; CtBP2 depletion abolishes NGF's suppressive effect on cyclin A1 expression.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, luciferase reporter assay, kinase assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, siRNA, and reporter assay; single lab with multiple methods\",\n      \"pmids\": [\"19668232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Drosophila Acinus (dacn) is required for stabilization of early endosomes, modulating Notch and Egfr signaling levels. Loss of dacn also inhibits autophagosome maturation in response to starvation, while dacn overexpression causes lethality through enhanced autophagy independent of the Tor pathway.\",\n      \"method\": \"Loss-of-function genetic screen, genetic interaction, endosomal trafficking assays, autophagy assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotypes in Drosophila ortholog; single lab with multiple readouts\",\n      \"pmids\": [\"20504956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Drosophila, Acinus (Acn) stability and basal autophagy regulation depend on proteolytic cleavage by the caspase Dcp-1 and on AKT1-mediated phosphorylation. Flies expressing stabilized Acn forms (phosphomimetic S641,731D or caspase-resistant D527A) exhibit enhanced basal autophagy, increased starvation resistance, reduced Huntingtin-induced neurodegeneration, and prolonged lifespan.\",\n      \"method\": \"Caspase loss-of-function, site-directed mutagenesis, autophagy flux assays, in vivo neurodegeneration models, lifespan analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic tools and in vivo functional readouts in Drosophila; single lab\",\n      \"pmids\": [\"25332163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Acinus L is a direct substrate of mTORC1; it was identified by overlapping quantitative phosphoproteomics (upon raptor inhibition) with endogenous mTOR interactomics, and confirmed by co-immunoprecipitation and MS-enhanced kinase assays showing insulin- and amino-acid-responsive phosphorylation.\",\n      \"method\": \"Quantitative phosphoproteomics, co-immunoprecipitation, MS-enhanced in vitro kinase assay\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct kinase assay plus orthogonal proteomics; single lab\",\n      \"pmids\": [\"25907765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Acinus functions in pre-mRNA splicing by enhancing inclusion of weak alternative cassette exons in a retinoic acid (RA)-dependent and -independent manner. The RRM domain is necessary for RA-dependent splicing activity, and RNPS1 represses the RA-independent splicing activity of Acinus. Acinus stimulates alternative 5' splice site usage of endogenous RARβ and Bcl-x transcripts.\",\n      \"method\": \"In vivo minigene splicing assays, domain deletion mutagenesis, endogenous pre-mRNA splicing assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigene assays with domain mutagenesis and endogenous target validation; single lab\",\n      \"pmids\": [\"25205379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"iCLIP mapping shows Acinus binds pre-mRNAs at a subset of suboptimal introns and also associates with spliced mRNAs, confirming its role as a peripheral EJC component. siRNA depletion of Acinus in HeLa cells preferentially disrupts inclusion of specific alternative cassette exons and faithful splicing of a subset of introns. Acinus directly regulates splicing of DFFA/ICAD transcript, a major DNA fragmentation regulator.\",\n      \"method\": \"iCLIP (cross-linking immunoprecipitation), siRNA depletion, RNA-seq\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide iCLIP binding map combined with siRNA-seq transcriptome; orthogonal methods confirm direct splicing role\",\n      \"pmids\": [\"27365209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Drosophila, Cdk5 phosphorylates Acinus at serine 437 to stabilize it and promote starvation-independent basal autophagy. Loss of Cdk5 or its cofactor p35 reduces pS437-Acn levels and basal autophagy. The phosphomimetic S437D mutation stabilizes Acn and promotes basal autophagy, and rescues neurodegeneration induced by polyQ proteins and Aβ42 (but not alpha-Synuclein).\",\n      \"method\": \"Genetic gain- and loss-of-function (Cdk5, p35 mutants), site-directed mutagenesis, autophagy assays, in vivo neurodegeneration models\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Cdk5 gain/loss-of-function with phospho-specific antibody and phosphomimetic/phospho-dead mutant rescue; replicated in multiple neurodegeneration models\",\n      \"pmids\": [\"29227247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The crystal structure of the human Acinus RRM domain was solved at 1.65 Å resolution, revealing a classical four-stranded antiparallel β-sheet with two flanking α-helices plus an additional C-terminal α-helix. The C-terminal helix partially occludes the ligand-binding surface of the β-sheet and harbors the caspase-3 target cleavage sequence, suggesting it shields RNA binding until proteolytic activation.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure at 1.65 Å with structural interpretation, but functional validation of the C-terminal helix occlusion model is hypothesized rather than experimentally confirmed in this paper\",\n      \"pmids\": [\"30042883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The sub-nuclear localization of Acinus isoforms differs: Acinus-S' colocalizes with SC35 in nuclear speckles (dependent on its C-terminal RS- and RD/E-rich region), while Acinus-L localizes diffusely in the nucleoplasm (dependent on its unique N-terminal SAP motif). The two isoforms influence each other's localization when co-expressed.\",\n      \"method\": \"Fluorescence microscopy, domain deletion/mutation constructs, co-localization with SC35 marker\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fluorescence localization with domain mapping via multiple deletion constructs; single lab\",\n      \"pmids\": [\"25079509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cdk5-mediated phosphorylation of Acn-S437 (Drosophila Acinus) is identified as a key regulator of basal autophagy, independent of metabolic stress. In nil1 (PPM-type phosphatase) loss-of-function animals, pS437-Acn levels are elevated, increasing neuronal autophagy and reducing polyQ accumulation in a Huntington's disease model.\",\n      \"method\": \"Genetic phosphatase screen, loss-of-function mutants, phospho-specific antibody, autophagy and neurodegeneration assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen plus loss-of-function confirmation with in vivo functional readout; single lab\",\n      \"pmids\": [\"29782227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Recurrent ACIN1-NUTM1 gene fusions (joining exons 3 or 4 of ACIN1 to exon 3 of NUTM1) were identified in non-KMT2A-rearranged infant ALL by transcriptome analysis. The fusion transcripts contain the functional SAP (SAF-A/B, Acinus, and PIAS) DNA-binding domain of ACIN1 and most of NUTM1.\",\n      \"method\": \"Transcriptome sequencing (RNA-seq), RT-PCR confirmation, cytogenetic analysis\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — identification of recurrent fusion by RNA-seq with RT-PCR confirmation in two cases; no functional mechanistic follow-up of the fusion protein\",\n      \"pmids\": [\"31515871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The RS (arginine/serine-rich) and RSB (RNPS1-SAP18-binding) domains of Acinus can modulate alternative splice site selection when tethered in an HIV-1 minigene reporter system, while full-length Acinus-S' does not affect splice site selection in this system.\",\n      \"method\": \"In vivo splicing assay with tethering constructs, minigene reporter\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (minigene tethering assay), with limited domain mapping\",\n      \"pmids\": [\"31070279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Elevated SRSF3 promotes inclusion of MBNL1 exons 5 and 7 via CA-rich exonic elements, and an increase in the resulting MBNL18 isoform shifts Acin1 splicing from the Acin1-S to the Acin1-L isoform, leading to diminished DNA fragmentation under oxidative stress in colorectal cancer cells.\",\n      \"method\": \"Whole-transcriptome analysis, minigene splicing assay, siRNA knockdown, DNA fragmentation assay\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome plus functional splicing and DNA fragmentation assays; single lab\",\n      \"pmids\": [\"33142236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Depletion of endogenous Acin1 isoforms activates brown adipogenic signatures in mouse C3H10T1/2 fibroblasts. Overexpression of Acin1-L versus Acin1-S exerts discriminative influences on brown adipogenesis through modulation of SRSF3 expression via an alternative splicing-coupled nonsense-mediated decay mechanism in a sequence-specific manner.\",\n      \"method\": \"siRNA knockdown, isoform overexpression, RNA-seq, splicing assays, brown adipogenesis differentiation assays\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq with functional differentiation assay and isoform-specific effects; single lab\",\n      \"pmids\": [\"32629174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The PPM-type phosphatase Nil (CG6036) counterbalances Cdk5-dependent phosphorylation of Acinus-S437 in Drosophila neurons. Loss of Nil enhances pS437-Acn levels and elevates neuronal autophagy. Cd2+ exposure inhibits this PPM-type phosphatase, elevating acn-S437 phosphorylation, which is required for increased neuronal autophagy and protection against Cd2+-induced cytotoxicity.\",\n      \"method\": \"Genetic phosphatase screen, loss-of-function mutants, phospho-specific antibody, cadmium exposure, autophagy and viability assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen identification plus loss-of-function confirmation with chemical (Cd2+) validation; single lab\",\n      \"pmids\": [\"35037620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Global deletion of Acin1 in mice causes embryonic lethality around E11.5, with developmental delays and increased apoptosis. Skeletal muscle myofiber-specific Acin1 knockout mice show enlarged myofibers, muscle damage, and regeneration. RNA-seq reveals that Acin1 deletion alters expression and splicing of genes crucial for muscle function, including splicing changes in genes associated with muscle disease and mitochondrial function, often producing immature or disease-associated splice variants.\",\n      \"method\": \"Conditional and global knockout mice, RNA-seq, immunohistochemistry, central nuclei counting\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo conditional KO with RNA-seq; single lab, single study\",\n      \"pmids\": [\"40269054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A point mutation in SRRM2 associated with ALS disrupts the protein-protein interaction between SRRM2 and the splicing factor ACIN1, revealing ACIN1 as a binding partner of SRRM2 in the nuclear speckle/splicing machinery.\",\n      \"method\": \"Endogenous gene point mutation in cell line, protein-protein interaction assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single interaction loss demonstrated in a preprint; no direct mechanistic follow-up on ACIN1 itself\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ACIN1 (Acinus) is a multifunctional nuclear RNA-binding protein that, upon caspase-3 cleavage, generates an active p17 fragment that induces apoptotic chromatin condensation and internucleosomal DNA fragmentation by activating PKC-delta and promoting H2B phosphorylation; this pro-apoptotic activity is antagonized by Akt-mediated phosphorylation at S422/S573 (which blocks caspase cleavage) and by binding partners such as AAC-11 and zyxin. In its non-apoptotic role, Acinus is a peripheral component of the exon junction complex (EJC) that directly binds pre-mRNA at suboptimal introns, regulates alternative splicing of numerous targets (including DFFA/ICAD, RARβ, and Bcl-x), and is a direct substrate of mTORC1 and SRPK2 (whose phosphorylation at S422 redistributes Acinus from nuclear speckles to nucleoplasm to upregulate cyclin A1); in Drosophila orthologs, Cdk5-dependent phosphorylation of the conserved serine 437 stabilizes Acinus and promotes starvation-independent basal autophagy that is critical for neuronal health.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACIN1 (Acinus) is a dual-function nuclear protein that couples apoptotic chromatin dynamics to pre-mRNA splicing regulation [#0, #12]. It was first identified as a caspase-3 substrate whose proteolytic cleavage generates an active p17 fragment that drives apoptotic nuclear changes [#0]; this activity is executed downstream by p17 binding to and activating PKC-delta, which promotes histone H2B phosphorylation, while ACIN1's principal apoptotic contribution is to internucleosomal DNA fragmentation rather than chromatin condensation per se [#2, #3]. The pro-apoptotic activity is gated by phosphorylation: Akt directly phosphorylates ACIN1 at serine 422 and serine 573 to render it resistant to caspase cleavage [#1], and this state is reinforced by partner proteins AAC-11 and zyxin that bind ACIN1 and protect it from cleavage [#4, #6]. In its non-apoptotic role, ACIN1 is a peripheral exon junction complex component that binds pre-mRNA at suboptimal introns and regulates inclusion of weak alternative cassette exons, controlling splicing of targets including RARβ, Bcl-x, and the DNA-fragmentation regulator DFFA/ICAD [#11, #12]. Its activity is shaped by kinase input—SRPK2 phosphorylation at S422 redistributes ACIN1 from nuclear speckles to nucleoplasm to upregulate cyclin A1 and drive cell-cycle progression [#5], and ACIN1 is a direct mTORC1 substrate [#10]—and by isoform-specific subnuclear targeting governed by its RS/RD-rich and SAP domains [#15]. In vivo, ACIN1 is essential for mouse embryonic development and for skeletal muscle homeostasis, where its loss alters splicing of muscle- and mitochondria-associated genes [#22]. Recurrent ACIN1-NUTM1 fusions retaining the ACIN1 SAP DNA-binding domain occur in infant acute lymphoblastic leukemia [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established ACIN1 as a caspase-3-activated nuclear factor required for apoptotic nuclear morphology, defining its founding role in cell death.\",\n      \"evidence\": \"in vitro reconstitution with immunodepletion and antisense knockdown\",\n      \"pmids\": [\"10490026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the downstream effectors of the cleaved fragment\", \"Relationship between chromatin condensation and DNA fragmentation left unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that Akt phosphorylation at S422/S573 shields ACIN1 from caspase cleavage, identifying a survival-signaling brake on its pro-apoptotic activation.\",\n      \"evidence\": \"in vitro kinase assay, phosphomimetic/phospho-dead mutagenesis, siRNA in apoptosis assays\",\n      \"pmids\": [\"16177823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling nuclear Akt activity not fully mapped\", \"Did not address splicing functions of phosphorylated ACIN1\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Reassigned ACIN1's apoptotic contribution from chromatin condensation to internucleosomal DNA fragmentation, refining the original 1999 model.\",\n      \"evidence\": \"inducible RNAi with intact-cell and cell-free apoptosis readouts\",\n      \"pmids\": [\"16537548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking ACIN1 to the DNA fragmentation machinery not defined here\", \"Isoform-specific contributions not dissected\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified the effector pathway of the ACIN1 p17 fragment—activation of PKC-delta leading to H2B phosphorylation—connecting cleavage to histone modification.\",\n      \"evidence\": \"reciprocal Co-IP, dominant-negative constructs, PKC-delta knockout MEFs, kinase assays\",\n      \"pmids\": [\"17721436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How H2B phosphorylation mechanically alters chromatin not resolved\", \"Mst1 contribution remained ambiguous\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed zyxin, recruited to the nucleus via Akt phosphorylation and 14-3-3γ, binds ACIN1-S and blocks its cleavage-dependent activity, adding a partner-mediated layer of apoptotic control.\",\n      \"evidence\": \"Co-IP, site-directed mutagenesis, nuclear fractionation, apoptosis assays\",\n      \"pmids\": [\"17572661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent replication\", \"Structural basis of zyxin-ACIN1 binding unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed a cell-cycle role: SRPK2 phosphorylation at S422 relocalizes ACIN1 from speckles to nucleoplasm to upregulate cyclin A1, linking ACIN1 phospho-state to transcription and proliferation.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, phosphomutants, siRNA, cell-cycle analysis\",\n      \"pmids\": [\"18559500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which nucleoplasmic ACIN1 drives cyclin A1 transcription unclear\", \"Whether speckle redistribution affects splicing not tested here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified AAC-11 as a leucine-zipper-dependent ACIN1 partner that protects against caspase cleavage, establishing a druggable anti-apoptotic interaction.\",\n      \"evidence\": \"Co-IP, in vitro caspase protection assay, siRNA, cell-permeable peptide competition\",\n      \"pmids\": [\"19387494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AAC-11 affects ACIN1 splicing function not examined\", \"In vivo relevance of the peptide not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked ACIN1 to transcriptional corepression via Akt-promoted CtBP2 binding downstream of NGF/TrkA, opposing cyclin A1 expression.\",\n      \"evidence\": \"Co-IP, siRNA, luciferase reporter, kinase assay\",\n      \"pmids\": [\"19668232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Direct vs indirect effect on the cyclin A1 promoter not separated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established a non-apoptotic role for the Drosophila ortholog in endosome stability and autophagosome maturation, broadening ACIN1 function into membrane trafficking and autophagy.\",\n      \"evidence\": \"loss-of-function genetic screen, genetic interactions, trafficking and autophagy assays in Drosophila\",\n      \"pmids\": [\"20504956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of trafficking role in mammals untested\", \"Molecular mechanism of endosome stabilization unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined isoform-specific subnuclear targeting of ACIN1, mapping speckle localization to the RS/RD-rich region and nucleoplasmic localization to the SAP-containing N-terminus.\",\n      \"evidence\": \"fluorescence microscopy with domain deletion constructs and SC35 co-localization\",\n      \"pmids\": [\"25079509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of cross-isoform localization influence unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated in Drosophila that caspase cleavage and Akt phosphorylation control Acinus stability to set basal autophagy, with stabilized forms conferring neuroprotection and longevity.\",\n      \"evidence\": \"caspase loss-of-function, phosphomimetic/cleavage-resistant mutants, autophagy flux, neurodegeneration and lifespan assays\",\n      \"pmids\": [\"25332163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian relevance of the autophagy-stability axis untested\", \"Molecular link from Acinus to autophagosome formation undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established ACIN1 as a sequence-context splicing enhancer of weak cassette exons, with the RRM required for retinoic-acid-dependent activity and RNPS1 repressing RA-independent activity.\",\n      \"evidence\": \"minigene splicing assays, domain deletion mutagenesis, endogenous RARβ/Bcl-x readouts\",\n      \"pmids\": [\"25205379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide target scope not addressed here\", \"Mechanism of RNPS1 repression unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified ACIN1-L as a direct, nutrient-responsive mTORC1 substrate, placing it under growth-signaling control.\",\n      \"evidence\": \"quantitative phosphoproteomics, mTOR interactomics, Co-IP, MS-enhanced kinase assay\",\n      \"pmids\": [\"25907765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of mTORC1 phosphorylation on splicing or apoptosis not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided a genome-wide binding and functional map confirming ACIN1 as a peripheral EJC component that binds suboptimal introns and directly regulates splicing of DFFA/ICAD, unifying its splicing and apoptosis roles.\",\n      \"evidence\": \"iCLIP, siRNA depletion, RNA-seq in HeLa cells\",\n      \"pmids\": [\"27365209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal link between ICAD splicing changes and apoptotic outcome not directly tested\", \"Determinants of suboptimal-intron selectivity unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed Cdk5/p35 phosphorylation of conserved S437 stabilizes Acinus and drives starvation-independent basal autophagy with selective neuroprotection in Drosophila.\",\n      \"evidence\": \"Cdk5/p35 gain- and loss-of-function, phospho-specific antibody, phosphomimetic rescue in neurodegeneration models\",\n      \"pmids\": [\"29227247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why protection is restricted to certain aggregating proteins not explained\", \"Mammalian ACIN1 S437 equivalent not validated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Solved the human ACIN1 RRM crystal structure, revealing a C-terminal helix that occludes the RNA-binding surface and harbors the caspase-3 cleavage site, suggesting cleavage unmasks RNA binding.\",\n      \"evidence\": \"X-ray crystallography at 1.65 Å\",\n      \"pmids\": [\"30042883\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Occlusion model not functionally validated in the study\", \"No structure of full-length or RNA-bound ACIN1\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the PPM-type phosphatase Nil as the counteracting enzyme controlling pS437-Acn levels, defining bidirectional phospho-regulation of autophagy.\",\n      \"evidence\": \"genetic phosphatase screen, loss-of-function mutants, phospho-specific antibody, autophagy/neurodegeneration assays\",\n      \"pmids\": [\"29782227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian phosphatase counterpart unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovered recurrent ACIN1-NUTM1 fusions retaining the ACIN1 SAP domain in infant ALL, implicating ACIN1 in oncogenic rearrangement.\",\n      \"evidence\": \"transcriptome sequencing with RT-PCR confirmation and cytogenetics\",\n      \"pmids\": [\"31515871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional characterization of the fusion protein\", \"Mechanism of leukemogenesis untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped RS and RSB domains as modulators of splice-site selection in a tethered reporter, providing low-resolution domain dissection of ACIN1 splicing activity.\",\n      \"evidence\": \"tethered minigene reporter splicing assay\",\n      \"pmids\": [\"31070279\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method, single lab without orthogonal validation\", \"Full-length ACIN1-S' showed no effect, leaving physiological relevance unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed an SRSF3/MBNL1-driven splicing switch shifts Acin1 from the S to the L isoform to suppress DNA fragmentation under oxidative stress in cancer cells, tying isoform choice to apoptotic resistance.\",\n      \"evidence\": \"whole-transcriptome analysis, minigene assay, siRNA, DNA fragmentation assay\",\n      \"pmids\": [\"33142236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular basis of isoform-specific fragmentation difference unresolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated isoform-specific ACIN1 control of brown adipogenesis through SRSF3 splicing-coupled NMD, extending its splicing regulation to cell differentiation.\",\n      \"evidence\": \"siRNA, isoform overexpression, RNA-seq, differentiation assays in fibroblasts\",\n      \"pmids\": [\"32629174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relevance to in vivo adipose biology untested\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established that the Nil phosphatase counterbalances Cdk5 at Acn-S437 and that environmental Cd2+ tunes this axis to control neuronal autophagy and survival.\",\n      \"evidence\": \"genetic phosphatase screen, loss-of-function, phospho-specific antibody, cadmium exposure, autophagy/viability assays\",\n      \"pmids\": [\"35037620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian conservation of the Cd2+-responsive axis untested\", \"Direct phosphatase-substrate biochemistry not reconstituted\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed ACIN1 is essential in vivo, with global knockout causing embryonic lethality and muscle-specific loss disrupting splicing of muscle and mitochondrial genes, establishing a developmental and tissue-homeostatic requirement.\",\n      \"evidence\": \"conditional and global knockout mice, RNA-seq, immunohistochemistry\",\n      \"pmids\": [\"40269054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal mis-spliced targets driving the muscle phenotype not isolated\", \"Embryonic lethality mechanism undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated ACIN1 as an SRRM2 interaction partner in the nuclear speckle/splicing machinery, with an ALS-associated SRRM2 mutation disrupting the interaction.\",\n      \"evidence\": \"endogenous point-mutation cell line and protein-protein interaction assay (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint without peer review and no mechanistic follow-up on ACIN1\", \"Functional consequence for ACIN1 splicing activity unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the apoptotic, splicing, cell-cycle, and autophagy functions of ACIN1 are integrated in a single mammalian cell—and which mis-spliced targets mediate its developmental essentiality—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking phospho-state, isoform, and localization to specific cellular outcomes\", \"Mammalian autophagy role of ACIN1 not directly demonstrated\", \"Functional consequences of the ACIN1-NUTM1 fusion uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [11, 12, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 15]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [5, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8, 9, 13]}\n    ],\n    \"complexes\": [\n      \"exon junction complex (EJC)\",\n      \"ASAP/PSAP complex (with RNPS1, SAP18)\"\n    ],\n    \"partners\": [\n      \"PRKCD\",\n      \"AKT1\",\n      \"SRPK2\",\n      \"AAC-11\",\n      \"ZYX\",\n      \"CTBP2\",\n      \"RNPS1\",\n      \"SRRM2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}