{"gene":"SUN2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2004,"finding":"SUN2 is an inner nuclear membrane (INM) protein in mammalian cells; a truncated form spanning amino acids 26–339 is sufficient for nuclear envelope localization, and its C-terminal SUN domain resides in the perinuclear lumenal space between inner and outer nuclear membranes.","method":"Recombinant EGFP/V5-tagged constructs, subcellular fractionation, electron microscopy, antibody co-localization with INM and nuclear pore markers","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (EM, fractionation, deletion constructs, co-localization) in a focused study establishing localization and domain requirements","pmids":["15082709"],"is_preprint":false},{"year":2007,"finding":"SUN2 specifically localizes to the nuclear envelope attachment sites of meiotic telomeres throughout their dynamic movement; EM reveals SUN2 is part of a membrane-spanning fibrillar complex interconnecting attached telomeres with cytoplasmic structures. This association does not require axial element assembly or A-type lamins.","method":"Immunofluorescence co-localization, electron microscopy, genetic ablation (lamin A-null, axial element-null mice)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal localization, ultrastructural EM, and genetic controls across multiple conditions in a single focused study","pmids":["17452644"],"is_preprint":false},{"year":2009,"finding":"SUN1 and SUN2 function redundantly to retain Syne-1/Nesprin-1 at the nuclear envelope in skeletal muscle cells; loss of both SUN1 and SUN2 disrupts Syne-1 NE localization and causes defective myonuclear positioning (both synaptic and nonsynaptic), demonstrating a dosage-dependent genetic interaction.","method":"Sun1 and Sun2 single and double knockout mice, immunofluorescence for Syne-1 at NE, assessment of myonuclear positioning","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined phenotypic readouts, gene dosage series, and molecular marker analysis replicated across multiple allele combinations","pmids":["19509342"],"is_preprint":false},{"year":2010,"finding":"INM targeting of SUN2 requires three redundant elements: (1) a classical NLS (cNLS) in its N-terminal nucleoplasmic domain, (2) an adjacent arginine cluster that mediates coatomer-dependent Golgi retrieval, and (3) the C-terminal lumenal SUN domain, making SUN2 the first mammalian INM protein relying on a cNLS, Golgi retrieval signal, and perinuclear domain for targeting.","method":"Deletion/mutation constructs, live-cell fluorescence imaging, coatomer binding assays, pharmacological Golgi disruption","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic mutagenesis combined with multiple functional localization assays and biochemical interaction studies in a single focused study","pmids":["20551905"],"is_preprint":false},{"year":2011,"finding":"Lamin A (but not lamin C) is required for NE localization of SUN2; overexpression of Rab5 redistributes SUN2 to endosomes via its SUN domain; endogenous SUN2 co-localizes with Rab5 and overexpression of SUN2 stimulates transferrin uptake while SUN2 knockdown attenuates it, indicating a role in endocytosis.","method":"Lamin A/C-deficient cells rescued with lamin A or C, Rab5 overexpression/dominant-negative transfection, transferrin uptake assay, co-localization imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional rescue experiments and endocytosis assay, but single lab and limited mechanistic depth on the Rab5 interaction","pmids":["21655223"],"is_preprint":false},{"year":2012,"finding":"SUN1 and SUN2 interact biochemically with the DNA-PK complex (Ku70/Ku80/DNA-PKcs) at the nuclear envelope; in Sun1/Sun2 double-knockout MEFs, activation of ATM and H2AX phosphorylation following DNA damage is impaired, and cells show premature S-phase arrest, increased apoptosis, and reduced perinuclear heterochromatin, placing SUN1/SUN2 upstream of DDR signaling.","method":"Sun1/Sun2 DKO mouse embryonic fibroblasts, biochemical co-immunoprecipitation screen, immunofluorescence for γH2AX/pATM, cell cycle FACS, DNAPK knockdown","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with phenotypic readout plus biochemical interaction, but interaction is from a screen and functional link to DNAPK is correlative","pmids":["22863315"],"is_preprint":false},{"year":2012,"finding":"Accumulation of farnesylated prelamin A (as in mandibuloacral dysplasia type A) alters SUN2 distribution at the NE, causing a disorganized lattice; treatment with statins (farnesyltransferase inhibitors) partially rescues proper SUN2 organization, establishing that SUN2 localization depends on correctly processed lamin A.","method":"Patient-derived MADA fibroblasts, statin/FTI drug treatment, immunofluorescence for SUN2","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological rescue plus patient cell lines, but mechanism is indirect (lamin A processing affecting SUN2 localization) and not dissected further","pmids":["22706480"],"is_preprint":false},{"year":2016,"finding":"SUN2 overexpression blocks HIV-1 infection between reverse transcription and nuclear entry in a capsid-specific manner; a single-amino-acid change in HIV capsid confers resistance; both HIV inhibition and nuclear shape deformation by SUN2 overexpression map to the nucleoplasmic/lamin-interacting domain of SUN2; cyclophilin A (CypA) is implicated in the SUN2-imposed block.","method":"Overexpression in cell lines and primary MDCs, passaging-selected capsid mutants, domain deletion mapping, chemical/genetic CypA inhibition, fluorescence imaging of nuclear shape","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (domain mapping, capsid mutant selection, CypA perturbation) in single lab","pmids":["26865710"],"is_preprint":false},{"year":2016,"finding":"Endogenous SUN2 at the inner nuclear membrane is required for CypA-dependent positive effects of wild-type HIV on reverse transcription and nuclear import of viral cDNA in primary CD4+ T cells; CypA-resistant capsid mutants are not restricted by SUN2.","method":"SUN2 siRNA knockdown in primary CD4+ T cells, CypA inhibitor/knockdown, infection with wild-type and capsid mutant HIV-1/HIV-2/SIVmac","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological perturbation in primary cells with mechanistic dissection, single lab","pmids":["27149839"],"is_preprint":false},{"year":2017,"finding":"SUN2 silencing in primary CD4+ T cells impairs their proliferative capacity, activation marker expression, and viability, and reduces viral protein expression in infected cells; the reduced HIV infection in SUN2-silenced CD4 T cells is independent of CypA.","method":"SUN2 siRNA in primary CD4+ T cells, proliferation assays, flow cytometry for activation markers, HIV infection assays with CypA inhibition","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary cell KD with multiple phenotypic readouts, CypA independence established; single lab","pmids":["28077629"],"is_preprint":false},{"year":2017,"finding":"CRISPR/Cas9-assembled CANC nanotubes captured both SUN1 and SUN2 from cell lysates, indicating physical interaction between HIV-1 capsid and SUN2; SUN2-/- CRISPR cells show a modest suppressive effect on HIV-1 infectivity.","method":"CRISPR/Cas9 knockout, in vitro capsid-nucleocapsid nanotube pulldown from cell lysates, HIV infectivity assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct pulldown assay plus genetic KO, but modest phenotype and single lab","pmids":["28747499"],"is_preprint":false},{"year":2018,"finding":"SUN2 maintains repressive chromatin at the HIV-1 5'-LTR by associating with lamin A/C; lamin A/C tethers SUN2 to nucleosomes 1 and 2 of the HIV-1 5'-LTR, blocking RNA Pol II phosphorylation and recruitment; SUN2 knockdown converts LTR chromatin to an active state and reactivates HIV from latency; TNF-α-induced reactivation disrupts the SUN2–lamin A/C association.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), SUN2 knockdown/overexpression, HIV latency reactivation assays, RNA Pol II phosphorylation analysis","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, and functional latency assays, but single lab","pmids":["29717016"],"is_preprint":false},{"year":2018,"finding":"Full-length SUN2 must trimerize (mediated by coiled-coil regions CC1 and CC2) to bind KASH-domain proteins; CC2-SUN alone forms an autoinhibited monomer; CC1–CC2 interplay releases autoinhibition; residue E452 on CC1 is involved in the monomer–trimer transition; Ca2+-dependent regulation of this transition is proposed.","method":"Molecular dynamics simulation (~1 µs), gel filtration analysis, mutagenesis of E452","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 1 (mutagenesis + gel filtration) / Moderate — computational model validated by gel filtration and mutagenesis, single lab; structural conclusion not from crystal structure","pmids":["29995584"],"is_preprint":false},{"year":2019,"finding":"SUN2-null mice develop cardiac hypertrophy with enhanced AKT/MAPK signaling but without fibrosis or upregulation of pathological hypertrophy markers; in the absence of SUN2, MAN1 (a negative regulator of TGFβ signaling) accumulates at the NE, suppressing profibrotic TGFβ signaling, uncoupling hypertrophy from fibrosis.","method":"Sun2-/- mice, cardiac morphometry, Western blot for AKT/MAPK, MAN1 and TGFβ pathway markers, nuclear fractionation","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotype and molecular pathway analysis, but mechanistic link to MAN1 is based on protein level changes without direct interaction proof; single lab","pmids":["31091167"],"is_preprint":false},{"year":2021,"finding":"SUN2 is a component of the spliceosome complex (associated with SNRPD2, SNRPD3, NHP2L1-containing complex) and is required for efficient sororin (CDCA5) pre-mRNA splicing; SUN2 depletion increases sororin intron 1 retention, downregulates SMC1/MAU2/ESPL1, and inhibits TNBC cell proliferation via disruption of sister chromatid cohesion.","method":"Pulldown followed by mass spectrometry (protein–protein interaction), RNAi screen, RT-PCR for intron retention, FACS, western blot","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-confirmed interaction plus functional splicing assay; single lab, novel finding for a nuclear membrane protein","pmids":["33648524"],"is_preprint":false},{"year":2022,"finding":"Casein Kinase 2 (CK2) phosphorylates SUN2, enabling binding of the SCFβTrCP ubiquitin ligase which ubiquitinates SUN2; ubiquitinated SUN2 is then extracted from the membrane by the AAA ATPase p97 and delivered to the proteasome for degradation; the phosphatase CTDNEP1 opposes CK2 to stabilize SUN2. Accumulation of non-degradable SUN2 causes aberrant nuclear architecture, DNA damage vulnerability, and increased lagging chromosomes.","method":"In vitro kinase/ubiquitination assays, co-immunoprecipitation, phosphomimetic/non-degradable mutants, p97 inhibition, CTDNEP1 knockdown, nuclear morphology and mitosis assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of phosphorylation and ubiquitination, mutagenesis, multiple orthogonal cell biology readouts in a single rigorous study","pmids":["36318477"],"is_preprint":false},{"year":2022,"finding":"FBXO2, an E3 ubiquitin ligase, recognizes glycosylated SUN2 and targets it for ubiquitin-proteasome-dependent degradation; this mechanism is driven upstream by transcription factor SOX6 promoting FBXO2 expression, defining a SOX6–FBXO2–SUN2 axis in ovarian cancer.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, FBXO2 overexpression/knockdown, glycosylation analysis, TCGA/GEO data integration","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical ubiquitination assay and Co-IP; single lab with multiple methods","pmids":["35525855"],"is_preprint":false},{"year":2022,"finding":"ECM rigidity upregulates SUN2 expression, and SUN2 in turn promotes metaphase-to-anaphase transition by facilitating mitotic spindle/astral microtubule organization; on soft ECM, low SUN2 levels perturb astral microtubule organization and delay anaphase onset.","method":"Polyacrylamide gels of defined stiffness, SUN2 knockdown/overexpression, live-cell mitosis imaging, microtubule organization analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined mechanical manipulation plus loss-of-function with specific mitotic phenotype, single lab","pmids":["36322767"],"is_preprint":false},{"year":2023,"finding":"Conserved cysteines in the SUN domain undergo KASH-dependent inter- and intra-molecular disulfide bond rearrangements; disruption of the terminal disulfide bond compromises SUN2 localization, turnover, LINC complex assembly, cytoskeletal organization, and cell migration; ER lumen components regulate SUN2 cysteine redox state.","method":"Conformation-specific SUN2 antibody, biochemical disulfide-bond analysis, cysteine mutants, FRAP, cell migration assays, pharmacological/genetic ER redox perturbation","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of key cysteines combined with biochemical, imaging, and functional cell biology readouts in a single focused study","pmids":["37188462"],"is_preprint":false},{"year":2023,"finding":"Aggregation of progerin at the NE triggers ER stress in a SUN2-dependent manner; the ability of SUN2 to cluster in the nuclear membrane is required for this ER stress induction, identifying SUN2 as a sensor/transducer of nucleoplasmic protein aggregates to the ER lumen.","method":"SUN2 knockdown/overexpression, SUN2 clustering mutants, ER stress reporter assays, live imaging in HGPS cells","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and domain-specific perturbation with functional ER stress readouts; single lab","pmids":["37210724"],"is_preprint":false},{"year":2024,"finding":"SUN2 (but not SUN1) is required for Zika, dengue, and Japanese encephalitis virus replication; mechanistically, SUN2 facilitates cytoskeleton rearrangement and replication organelle formation by mediating the interaction between cytoskeletal actin and viral NS1; dominant-negative nesprin-1/2 (which connect SUN2 to cytoskeleton) reduces actin–NS1 interaction and viral replication.","method":"CRISPR/Cas9 SUN2 KO, co-immunoprecipitation of actin with NS1, dominant-negative nesprin constructs, viral RNA synthesis assays, neonatal mouse in vivo infection model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO plus biochemical interaction plus dominant-negative genetics plus in vivo mouse model; multiple orthogonal methods replicated across three viral species","pmids":["38177122"],"is_preprint":false},{"year":2024,"finding":"Calcium elevations trigger rapid nuclear actin assembly requiring SUN2 independently of its LINC complex role; SUN2 co-localizes and associates with the formin/actin nucleator INF2 at the nuclear envelope in a calcium-regulated manner; SUN2 is required for active RNA Pol II clustering in response to calcium elevations.","method":"Calcium stimulation, SUN2 knockdown/knockout, co-immunoprecipitation of SUN2 with INF2, fluorescence imaging of nuclear actin and RNA Pol II clusters","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, genetic KD with specific functional readout (RNA Pol II clustering), single lab","pmids":["39317734"],"is_preprint":false},{"year":2025,"finding":"Paclitaxel induces nuclear aberrations in interphase through SUN2-dependent disruption of lamin A/C levels and organization; SUN2 is required for lamin A/C reduction upon paclitaxel treatment and is regulated by polyubiquitylation; aberrant microtubule-vimentin bundles form during paclitaxel treatment coincident with SUN2-mediated nuclear deformation.","method":"Optical imaging, electron cryo-tomography, SUN2 knockdown/overexpression, lamin A/C quantification, ubiquitination assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cryo-ET structural imaging plus genetic KD and biochemical ubiquitination; single lab, novel finding","pmids":["41367359"],"is_preprint":false},{"year":2025,"finding":"FRET-based nuclear tension sensors (NuTS2) placed across SUN2 measure tension forces transmitted through the LINC complex in living cells; NuTS2 reveals that force transmission across SUN2 increases with cell contractility and matrix stiffness, occurs dynamically during adhesion, migration, and nuclear squeeze, and shows a gradient increasing from posterior to anterior in zebrafish notochord cells as vacuoles expand.","method":"Genetically encoded FRET tension sensors inserted into SUN2, live-cell imaging, zebrafish notochord in vivo imaging, mechanical perturbations","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biophysical measurement with FRET sensor in cells and in vivo; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.02.17.638756"],"is_preprint":true},{"year":2026,"finding":"Sun2 is required for stiffness-dependent upregulation of ECM protein genes in lung fibroblasts; loss of Sun2 prevents lung fibrosis in bleomycin-treated mice without impairing myofibroblast formation or TGFβ responsiveness per se, indicating Sun2 acts as a mechanical coincidence detector for ECM gene induction.","method":"Sun2 knockout mice, bleomycin lung fibrosis model, substrate stiffness gels, gene expression profiling, TGFβ treatment","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with defined fibrosis phenotype and mechanistic in vitro dissection; preprint, not peer-reviewed","pmids":["41889916"],"is_preprint":true},{"year":2026,"finding":"SUN2 mediates stiffness-dependent epigenetic remodeling in dermal fibroblasts; loss of Sun2 prevents bleomycin-induced skin fibrosis and abolishes stiffness-induced nuclear size changes and fibrotic gene expression; mechanistically, Sun2 is required for mechanical induction of the histone methyltransferase EZH2, defining three Sun2-dependent mechanosensitive chromatin states.","method":"Sun2 knockout mice, bleomycin skin fibrosis model, substrate stiffness gels, histone ChIP for H3K27me3, EZH2 western blot/knockdown, nuclear morphometry","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO plus chromatin-level mechanistic dissection; preprint, not peer-reviewed","pmids":["41890082"],"is_preprint":true},{"year":2026,"finding":"Farnesylated prelamin A variants reduce diffusional mobilities of nesprin-2 and SUN2 at the NE and impair their function in actin-driven nuclear rearward movement for cell polarization in a farnesylation-dependent manner; short C-terminal tail fragments of prelamin A variants are sufficient to disrupt polarity, identifying inhibition of the nesprin-2/SUN2 LINC complex as the common mechanism in prelamin A-related premature aging syndromes.","method":"FRAP for nesprin-2 and SUN2 mobility, cell polarization assays, expression of farnesylation-deficient prelamin A mutants, tail fragment expression","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP plus domain-specific mutagenesis with functional polarization readout; single lab","pmids":["42011117"],"is_preprint":false}],"current_model":"SUN2 is an integral inner nuclear membrane protein whose N-terminal nucleoplasmic cNLS, coatomer-retrieval signal, and lumenal SUN domain collectively target it to the INM, where it forms trimers (regulated by CC1–CC2 coiled-coil interplay and disulfide bond rearrangements in the SUN domain) to bind KASH-domain nesprins and thereby bridge the nucleoskeleton to the cytoskeleton; its stability is controlled by CK2-mediated phosphorylation triggering SCFβTrCP ubiquitination and p97-dependent proteasomal degradation (opposed by CTDNEP1), as well as by FBXO2-mediated recognition of glycosylated SUN2; through these LINC interactions SUN2 (i) positions nuclei in skeletal muscle by retaining Syne-1/Nesprin-1 at the NE, (ii) transmits mechanical forces from ECM stiffness to drive mitotic spindle organization, fibrotic gene programs (via EZH2/chromatin), and endothelial homeostasis, (iii) tethers meiotic telomeres to the NE for bouquet formation, (iv) supports DNA-damage responses by interacting with the DNA-PK complex, (v) associates with INF2 at the NE in a calcium-regulated manner to promote nuclear actin polymerization and RNA Pol II clustering, (vi) modulates HIV infection at the nuclear envelope through capsid/CypA-dependent and lamin A/C–chromatin-dependent mechanisms, and (vii) facilitates flavivirus replication by mediating NS1–actin cytoskeletal interactions."},"narrative":{"mechanistic_narrative":"SUN2 is an integral inner nuclear membrane (INM) protein that forms the nucleoplasmic half of the LINC complex, physically coupling the nucleoskeleton to the cytoskeleton and serving as a node for mechanotransduction, nuclear positioning, and genome organization [PMID:15082709, PMID:19509342]. It localizes to the INM through three redundant signals—an N-terminal classical NLS, an adjacent coatomer-dependent Golgi-retrieval arginine cluster, and the C-terminal lumenal SUN domain—and its NE retention further depends on correctly processed lamin A [PMID:20551905, PMID:21655223]. Functional LINC assembly requires SUN2 to convert from an autoinhibited monomer to a CC1/CC2 coiled-coil-stabilized trimer competent to bind KASH-domain nesprins, a transition reinforced by KASH-dependent disulfide-bond rearrangements among conserved SUN-domain cysteines whose redox state is set by the ER lumen [PMID:29995584, PMID:37188462]. Through these nesprin connections SUN2 retains Syne-1/Nesprin-1 at the muscle NE to position myonuclei and tethers meiotic telomeres to the envelope for their dynamic movement [PMID:17452644, PMID:19509342]. SUN2 transmits mechanical force from ECM stiffness across the NE, driving mitotic spindle and astral-microtubule organization, stiffness-dependent fibrotic gene programs via EZH2-mediated chromatin remodeling, and direct LINC tension measurable in living cells [PMID:36322767, PMID:bio_10.1101_2025.02.17.638756, PMID:41890082]. SUN2 also gates genome function and stress responses—supporting DNA-damage signaling via the DNA-PK complex, associating with the actin nucleator INF2 to drive calcium-triggered nuclear actin assembly and RNA Pol II clustering, and participating in pre-mRNA splicing of sororin [PMID:22863315, PMID:39317734, PMID:33648524]. SUN2 abundance is tightly controlled by CK2 phosphorylation that licenses SCFβTrCP ubiquitination and p97-dependent proteasomal extraction, opposed by the phosphatase CTDNEP1, and by FBXO2-mediated recognition of glycosylated SUN2 [PMID:36318477, PMID:35525855]. In viral infection SUN2 both restricts and supports HIV-1 at the nuclear envelope through capsid/CypA- and lamin A/C–chromatin-dependent mechanisms and is required for flavivirus replication by bridging actin to viral NS1 [PMID:26865710, PMID:29717016, PMID:38177122].","teleology":[{"year":2004,"claim":"Established that SUN2 is an INM protein with its SUN domain in the perinuclear lumen, defining the topology required for any nucleoskeleton-cytoskeleton bridging function.","evidence":"Tagged deletion constructs, fractionation, EM, and marker co-localization in mammalian cells","pmids":["15082709"],"confidence":"High","gaps":["Binding partners on either membrane face not yet identified","No functional readout of LINC bridging"]},{"year":2007,"claim":"Showed SUN2 marks NE attachment sites of meiotic telomeres within a membrane-spanning fibrillar complex, the first concrete role linking SUN2 to coupling nuclear contents to cytoplasmic structures.","evidence":"Immunofluorescence, EM, and lamin A-null / axial element-null mouse genetics","pmids":["17452644"],"confidence":"High","gaps":["Cytoplasmic partner mediating telomere movement not defined","Whether SUN2 is essential versus redundant for bouquet formation unresolved"]},{"year":2009,"claim":"Demonstrated SUN1/SUN2 functional redundancy in retaining nesprin at the NE and positioning myonuclei, establishing the genetic logic of LINC dosage in tissue.","evidence":"Sun1/Sun2 single and double knockout mice with nesprin localization and myonuclear positioning readouts","pmids":["19509342"],"confidence":"High","gaps":["Direct SUN2–Syne-1 interaction interface not mapped here","Tissue specificity of redundancy unclear"]},{"year":2010,"claim":"Answered how SUN2 reaches the INM, revealing reliance on a cNLS, a coatomer-retrieval signal, and the SUN domain together.","evidence":"Systematic mutagenesis, live imaging, coatomer-binding and Golgi-disruption assays","pmids":["20551905"],"confidence":"High","gaps":["Relative weight of each signal in physiological context not quantified"]},{"year":2011,"claim":"Linked SUN2 NE retention to lamin A and implicated SUN2 in endocytic transferrin uptake via Rab5, broadening its localization dependencies and possible roles.","evidence":"Lamin A/C rescue, Rab5 perturbation, and transferrin uptake assays","pmids":["21655223"],"confidence":"Medium","gaps":["Mechanism of SUN2–Rab5 endocytic role shallow","Single lab; physiological relevance of endosomal pool unclear"]},{"year":2012,"claim":"Placed SUN1/SUN2 upstream of DNA-damage signaling through physical association with the DNA-PK complex and DDR phenotypes in DKO cells.","evidence":"Sun1/Sun2 DKO MEFs, Co-IP screen, γH2AX/pATM imaging, DNAPK knockdown","pmids":["22863315"],"confidence":"Medium","gaps":["Interaction from a screen; reciprocal validation limited","Functional link to DNAPK correlative"]},{"year":2016,"claim":"Defined SUN2 as a modulator of HIV-1 at the nuclear envelope, with capsid/CypA-dependent restriction mapping to its lamin-interacting nucleoplasmic domain and an opposing endogenous requirement for productive infection.","evidence":"Overexpression and knockdown in cell lines and primary CD4+ T cells, capsid mutant selection, CypA perturbation","pmids":["26865710","27149839"],"confidence":"Medium","gaps":["Dual restrictive/supportive role mechanistically unreconciled","Direct capsid contact not shown in these studies"]},{"year":2017,"claim":"Showed direct physical capture of SUN2 by HIV-1 capsid and that SUN2 also supports CD4+ T-cell proliferation and viability, complicating its net effect on infection.","evidence":"CRISPR knockout, CANC nanotube pulldown, proliferation/activation assays","pmids":["28747499","28077629"],"confidence":"Medium","gaps":["Phenotypes modest","Whether T-cell fitness effect confounds infection readouts"]},{"year":2018,"claim":"Revealed a chromatin-level role: SUN2 with lamin A/C tethers and silences the HIV-1 5'-LTR, blocking RNA Pol II recruitment and enforcing latency.","evidence":"Co-IP, ChIP, knockdown/overexpression, latency reactivation assays","pmids":["29717016"],"confidence":"Medium","gaps":["Generalization beyond LTR to host genes untested","Single lab"]},{"year":2018,"claim":"Provided the structural logic of LINC assembly, showing trimerization driven by CC1/CC2 interplay relieves SUN-domain autoinhibition to enable KASH binding.","evidence":"Molecular dynamics simulation, gel filtration, E452 mutagenesis","pmids":["29995584"],"confidence":"Medium","gaps":["No crystal structure of full-length trimer","Proposed Ca2+ regulation not directly demonstrated"]},{"year":2021,"claim":"Uncovered an unexpected spliceosome-associated function, with SUN2 required for sororin pre-mRNA splicing and sister chromatid cohesion in cancer cells.","evidence":"Pulldown-MS, RNAi, intron-retention RT-PCR, FACS in TNBC cells","pmids":["33648524"],"confidence":"Medium","gaps":["How an INM protein engages the spliceosome unexplained","Single lab; cancer-specific context"]},{"year":2022,"claim":"Defined the proteostatic control of SUN2: a CK2–SCFβTrCP–p97 degradation axis opposed by CTDNEP1, with a parallel FBXO2/SOX6 route for glycosylated SUN2.","evidence":"In vitro kinase/ubiquitination reconstitution, degron mutants, p97 inhibition, CTDNEP1 knockdown; separate FBXO2 Co-IP and ubiquitination assays","pmids":["36318477","35525855"],"confidence":"High","gaps":["Trigger for CK2 phosphorylation in vivo unclear","Crosstalk between the two degradation routes unknown"]},{"year":2022,"claim":"Connected SUN2 to mechanically driven mitosis, with ECM stiffness raising SUN2 to organize astral microtubules and license anaphase onset.","evidence":"Defined-stiffness gels, SUN2 knockdown/overexpression, live mitosis imaging","pmids":["36322767"],"confidence":"Medium","gaps":["Molecular link from SUN2 to spindle apparatus not resolved","Single lab"]},{"year":2023,"claim":"Established redox control of SUN2, with KASH-dependent disulfide rearrangements governing localization, turnover, LINC assembly, and migration.","evidence":"Conformation-specific antibody, cysteine mutants, FRAP, migration assays, ER redox perturbation","pmids":["37188462"],"confidence":"High","gaps":["ER lumenal oxidoreductase responsible not identified"]},{"year":2023,"claim":"Identified SUN2 as a transducer of nucleoplasmic protein aggregation to the ER, with its clustering required for progerin-triggered ER stress.","evidence":"Knockdown/overexpression, clustering mutants, ER stress reporters in HGPS cells","pmids":["37210724"],"confidence":"Medium","gaps":["Signal relayed across membrane to ER lumen undefined","Single lab"]},{"year":2024,"claim":"Showed SUN2-specific support of flavivirus replication by bridging cytoskeletal actin to viral NS1 for replication organelle formation.","evidence":"CRISPR KO, actin–NS1 Co-IP, dominant-negative nesprin, viral RNA assays, neonatal mouse model across three viruses","pmids":["38177122"],"confidence":"High","gaps":["Whether SUN2 directly contacts NS1 versus via actin unresolved"]},{"year":2024,"claim":"Revealed a LINC-independent role for SUN2 in calcium-triggered nuclear actin assembly via INF2, coupling calcium signaling to RNA Pol II clustering.","evidence":"Calcium stimulation, knockdown/knockout, SUN2–INF2 Co-IP, nuclear actin and Pol II imaging","pmids":["39317734"],"confidence":"Medium","gaps":["How INM SUN2 nucleates nucleoplasmic actin geometrically unclear","Single lab"]},{"year":2025,"claim":"Directly measured LINC tension across SUN2 in living cells, showing force transmission scales with contractility and stiffness and varies spatially in vivo.","evidence":"FRET tension sensors inserted into SUN2, live-cell and zebrafish notochord imaging (preprint)","pmids":["bio_10.1101_2025.02.17.638756"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Sensor insertion effects on native function not fully controlled"]},{"year":2026,"claim":"Defined SUN2 as a mechanical coincidence detector driving stiffness-dependent fibrotic gene programs through EZH2/H3K27me3 chromatin remodeling, with loss preventing organ fibrosis in vivo.","evidence":"Sun2 knockout mice, bleomycin lung and skin fibrosis models, stiffness gels, EZH2/H3K27me3 ChIP and expression profiling (preprints)","pmids":["41889916","41890082"],"confidence":"Medium","gaps":["Preprints, not peer-reviewed","Path from LINC tension to EZH2 induction not molecularly traced"]},{"year":2026,"claim":"Connected SUN2 mobility defects to laminopathy mechanism, with farnesylated prelamin A immobilizing the nesprin-2/SUN2 LINC complex to impair actin-driven nuclear positioning and cell polarization.","evidence":"FRAP of nesprin-2 and SUN2, farnesylation-deficient prelamin A and tail-fragment expression, polarization assays","pmids":["42011117"],"confidence":"Medium","gaps":["Direct prelamin A–SUN2 contact versus indirect lamina effect not separated","Single lab"]},{"year":null,"claim":"How SUN2's diverse roles—LINC bridging, mechanosensing-to-chromatin signaling, splicing, nuclear actin, and viral modulation—are coordinated within a single protein, and how force across the SUN domain is converted into transcriptional and chromatin outputs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking mechanical input to chromatin/transcriptional output","Structural basis of force transmission through trimeric SUN2 unsolved","Reconciliation of restrictive versus supportive viral roles missing"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,12,18]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[17,19,23]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[20,21]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,12]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1,11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[18,19]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[11,25]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[14,17]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[15,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[20,24,25]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[19,23]}],"complexes":["LINC complex","spliceosome"],"partners":["SYNE1","SYNE2","LMNA","INF2","FBXO2","CTDNEP1","PRKDC","VCP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UH99","full_name":"SUN domain-containing protein 2","aliases":["Protein unc-84 homolog B","Rab5-interacting protein","Rab5IP","Sad1/unc-84 protein-like 2"],"length_aa":717,"mass_kda":80.3,"function":"As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton. The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning. Specifically, SYNE2 and SUN2 assemble in arrays of transmembrane actin-associated nuclear (TAN) lines which are bound to F-actin cables and couple the nucleus to retrograde actin flow during actin-dependent nuclear movement. Required for interkinetic nuclear migration (INM) and essential for nucleokinesis and centrosome-nucleus coupling during radial neuronal migration in the cerebral cortex and during glial migration. Required for nuclear migration in retinal photoreceptor progenitors implicating association with cytoplasmic dynein-dynactin and kinesin motor complexes, and probably B-type lamins; SUN1 and SUN2 seem to act redundantly. The SUN1/2:KASH5 LINC complex couples telomeres to microtubules during meiosis; SUN1 and SUN2 seem to act at least partial redundantly. Anchors chromosome movement in the prophase of meiosis and is involved in selective gene expression of coding and non-coding RNAs needed for gametogenesis. Required for telomere attachment to nuclear envelope and gametogenesis. May also function on endocytic vesicles as a receptor for RAB5-GDP and participate in the activation of RAB5","subcellular_location":"Nucleus inner membrane; Nucleus envelope; Endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9UH99/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SUN2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ARL6IP6","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SUN2","total_profiled":1310},"omim":[{"mim_id":"618484","title":"ARTHROGRYPOSIS MULTIPLEX CONGENITA 3, MYOGENIC TYPE; AMC3","url":"https://www.omim.org/entry/618484"},{"mim_id":"617676","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 3; PSMD3","url":"https://www.omim.org/entry/617676"},{"mim_id":"615535","title":"SPECTRIN REPEAT-CONTAINING NUCLEAR ENVELOPE PROTEIN 4; SYNE4","url":"https://www.omim.org/entry/615535"},{"mim_id":"614513","title":"TORSIN 1A-INTERACTING PROTEIN 2; TOR1AIP2","url":"https://www.omim.org/entry/614513"},{"mim_id":"613569","title":"SAD1 AND UNC84 DOMAIN-CONTAINING PROTEIN 2; SUN2","url":"https://www.omim.org/entry/613569"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SUN2"},"hgnc":{"alias_symbol":[],"prev_symbol":["UNC84B"]},"alphafold":{"accession":"Q9UH99","domains":[{"cath_id":"2.60.120.260","chopping":"547-714","consensus_level":"high","plddt":87.4141,"start":547,"end":714},{"cath_id":"1.20.5","chopping":"328-454","consensus_level":"medium","plddt":87.4125,"start":328,"end":454}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UH99","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UH99-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UH99-F1-predicted_aligned_error_v6.png","plddt_mean":67.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SUN2","jax_strain_url":"https://www.jax.org/strain/search?query=SUN2"},"sequence":{"accession":"Q9UH99","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UH99.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UH99/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UH99"}},"corpus_meta":[{"pmid":"19509342","id":"PMC_19509342","title":"SUN1 and SUN2 play critical but partially redundant roles in anchoring nuclei in skeletal muscle cells in mice.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19509342","citation_count":199,"is_preprint":false},{"pmid":"15082709","id":"PMC_15082709","title":"Sun2 is a novel mammalian inner nuclear membrane protein.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15082709","citation_count":170,"is_preprint":false},{"pmid":"25210889","id":"PMC_25210889","title":"Muscular dystrophy-associated SUN1 and SUN2 variants disrupt nuclear-cytoskeletal connections and myonuclear organization.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25210889","citation_count":138,"is_preprint":false},{"pmid":"17452644","id":"PMC_17452644","title":"Transmembrane protein Sun2 is involved in tethering mammalian meiotic telomeres to the nuclear envelope.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17452644","citation_count":134,"is_preprint":false},{"pmid":"26175118","id":"PMC_26175118","title":"Global loss of a nuclear lamina component, lamin A/C, and LINC complex components SUN1, SUN2, and nesprin-2 in breast cancer.","date":"2015","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26175118","citation_count":122,"is_preprint":false},{"pmid":"22863315","id":"PMC_22863315","title":"Inner nuclear envelope proteins SUN1 and SUN2 play a prominent role in the DNA damage response.","date":"2012","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/22863315","citation_count":90,"is_preprint":false},{"pmid":"20551905","id":"PMC_20551905","title":"A classical NLS and the SUN domain contribute to the targeting of SUN2 to the inner nuclear membrane.","date":"2010","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/20551905","citation_count":79,"is_preprint":false},{"pmid":"26658802","id":"PMC_26658802","title":"SUN2 exerts tumor suppressor functions by suppressing the Warburg effect in lung cancer.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26658802","citation_count":78,"is_preprint":false},{"pmid":"30282980","id":"PMC_30282980","title":"Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30282980","citation_count":55,"is_preprint":false},{"pmid":"35525855","id":"PMC_35525855","title":"FBXO2 targets glycosylated SUN2 for ubiquitination and degradation to promote ovarian cancer development.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35525855","citation_count":44,"is_preprint":false},{"pmid":"27149839","id":"PMC_27149839","title":"Nuclear Envelope Protein SUN2 Promotes Cyclophilin-A-Dependent Steps of HIV Replication.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27149839","citation_count":42,"is_preprint":false},{"pmid":"26865710","id":"PMC_26865710","title":"SUN2 Overexpression Deforms Nuclear Shape and Inhibits HIV.","date":"2016","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26865710","citation_count":41,"is_preprint":false},{"pmid":"36318477","id":"PMC_36318477","title":"Regulated degradation of the inner nuclear membrane protein SUN2 maintains nuclear envelope architecture and function.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36318477","citation_count":37,"is_preprint":false},{"pmid":"33648524","id":"PMC_33648524","title":"Splicing factors control triple-negative breast cancer cell mitosis through SUN2 interaction and sororin intron retention.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33648524","citation_count":35,"is_preprint":false},{"pmid":"21655223","id":"PMC_21655223","title":"Subcellular localization of SUN2 is regulated by lamin A and Rab5.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21655223","citation_count":29,"is_preprint":false},{"pmid":"29717016","id":"PMC_29717016","title":"SUN2 Modulates HIV-1 Infection and Latency through Association with Lamin A/C To Maintain the Repressive Chromatin.","date":"2018","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/29717016","citation_count":27,"is_preprint":false},{"pmid":"24832085","id":"PMC_24832085","title":"Downregulation of SUN2, a novel tumor suppressor, mediates miR-221/222-induced malignancy in central nervous system embryonal tumors.","date":"2014","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/24832085","citation_count":27,"is_preprint":false},{"pmid":"31091167","id":"PMC_31091167","title":"Ablation of SUN2-containing LINC complexes drives cardiac hypertrophy without interstitial fibrosis.","date":"2019","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/31091167","citation_count":26,"is_preprint":false},{"pmid":"22706480","id":"PMC_22706480","title":"Altered chromatin organization and SUN2 localization in mandibuloacral dysplasia are rescued by drug treatment.","date":"2012","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22706480","citation_count":26,"is_preprint":false},{"pmid":"37198162","id":"PMC_37198162","title":"Nuclear softening mediated by Sun2 suppression delays mechanical stress-induced cellular senescence.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37198162","citation_count":24,"is_preprint":false},{"pmid":"28077629","id":"PMC_28077629","title":"SUN2 Silencing Impairs CD4 T Cell Proliferation and Alters Sensitivity to HIV-1 Infection Independently of Cyclophilin A.","date":"2017","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/28077629","citation_count":22,"is_preprint":false},{"pmid":"33931868","id":"PMC_33931868","title":"Downregulation of SUN2 promotes metastasis of colon cancer by activating BDNF/TrkB signalling by interacting with SIRT1.","date":"2021","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33931868","citation_count":19,"is_preprint":false},{"pmid":"28747499","id":"PMC_28747499","title":"Effects of Inner Nuclear Membrane Proteins SUN1/UNC-84A and SUN2/UNC-84B on the Early Steps of HIV-1 Infection.","date":"2017","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/28747499","citation_count":19,"is_preprint":false},{"pmid":"29995584","id":"PMC_29995584","title":"A molecular model for LINC complex regulation: activation of SUN2 for KASH binding.","date":"2018","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/29995584","citation_count":19,"is_preprint":false},{"pmid":"30675193","id":"PMC_30675193","title":"SUN2: A potential therapeutic target in cancer.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30675193","citation_count":17,"is_preprint":false},{"pmid":"38177122","id":"PMC_38177122","title":"Nuclear membrane protein SUN2 promotes replication of flaviviruses through modulating cytoskeleton reorganization mediated by NS1.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38177122","citation_count":17,"is_preprint":false},{"pmid":"37210724","id":"PMC_37210724","title":"Activation of endoplasmic reticulum stress in premature aging via the inner nuclear membrane protein SUN2.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37210724","citation_count":17,"is_preprint":false},{"pmid":"29163775","id":"PMC_29163775","title":"Loss of Sun2 promotes the progression of prostate cancer by regulating fatty acid oxidation.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29163775","citation_count":17,"is_preprint":false},{"pmid":"36322767","id":"PMC_36322767","title":"SUN2 regulates mitotic duration in response to extracellular matrix rigidity.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36322767","citation_count":17,"is_preprint":false},{"pmid":"37188462","id":"PMC_37188462","title":"Disulfide bond in SUN2 regulates dynamic remodeling of LINC complexes at the nuclear envelope.","date":"2023","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/37188462","citation_count":13,"is_preprint":false},{"pmid":"39317734","id":"PMC_39317734","title":"SUN2 mediates calcium-triggered nuclear actin polymerization to cluster active RNA polymerase II.","date":"2024","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/39317734","citation_count":11,"is_preprint":false},{"pmid":"35435724","id":"PMC_35435724","title":"SUN2 Modulates the Propagation of HSV-1.","date":"2022","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/35435724","citation_count":6,"is_preprint":false},{"pmid":"33384835","id":"PMC_33384835","title":"Elevated Sad1 and UNC84 Domain Containing 2 (SUN2) level inhibits cell growth and aerobic glycolysis in oral cancer through reducing the expressions of glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA).","date":"2020","source":"Journal of dental sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33384835","citation_count":6,"is_preprint":false},{"pmid":"37421143","id":"PMC_37421143","title":"Physcomitrium patens SUN2 Mediates MTOC Association with the Nuclear Envelope and Facilitates Chromosome Alignment during Spindle Assembly.","date":"2023","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37421143","citation_count":5,"is_preprint":false},{"pmid":"39288611","id":"PMC_39288611","title":"Long non-coding RNA SUN2-AS1 acts as a negative regulator of ISGs transcription to promote flavivirus infection.","date":"2024","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/39288611","citation_count":1,"is_preprint":false},{"pmid":"41308440","id":"PMC_41308440","title":"SUN2 downregulation promotes breast cancer cell proliferation via NFATC4 upregulation.","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41308440","citation_count":0,"is_preprint":false},{"pmid":"41367359","id":"PMC_41367359","title":"Paclitaxel compromises nuclear integrity in interphase through SUN2-mediated cytoskeletal coupling.","date":"2026","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/41367359","citation_count":0,"is_preprint":false},{"pmid":"41890082","id":"PMC_41890082","title":"SUN2 mediates epigenetic remodeling to drive mechanotransduction during skin fibrosis.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41890082","citation_count":0,"is_preprint":false},{"pmid":"42239109","id":"PMC_42239109","title":"Nuclear SUN2 coordinates endothelial cell-matrix interactions to regulate blood vessel homeostasis and barrier function.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42239109","citation_count":0,"is_preprint":false},{"pmid":"41889916","id":"PMC_41889916","title":"Loss of Sun2 ablates nuclear mechanosensing-driven extracellular matrix production and mitigates lung fibrosis.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41889916","citation_count":0,"is_preprint":false},{"pmid":"42011117","id":"PMC_42011117","title":"Farnesylated prelamin A induces fibroblast polarity defects in premature aging disorders by inhibiting nesprin-2-SUN2 LINC complex function.","date":"2026","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/42011117","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.17.638756","title":"Dissecting Force Transmission across SUN Proteins Using Nuclear Tension Sensors","date":"2025-02-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.17.638756","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.15.633301","title":"Elevated SUN1 promotes aging-related polarity defects through mechanical coupling microtubules to the nuclear lamina","date":"2025-01-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.15.633301","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.03.686286","title":"Intrinsic mechanotransduction during apical constriction licenses lineage competence in pluripotent stem cells","date":"2025-11-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.03.686286","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22636,"output_tokens":7075,"usd":0.087016,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16417,"output_tokens":5932,"usd":0.115193,"stage2_stop_reason":"end_turn"},"total_usd":0.202209,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"SUN2 is an inner nuclear membrane (INM) protein in mammalian cells; a truncated form spanning amino acids 26–339 is sufficient for nuclear envelope localization, and its C-terminal SUN domain resides in the perinuclear lumenal space between inner and outer nuclear membranes.\",\n      \"method\": \"Recombinant EGFP/V5-tagged constructs, subcellular fractionation, electron microscopy, antibody co-localization with INM and nuclear pore markers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (EM, fractionation, deletion constructs, co-localization) in a focused study establishing localization and domain requirements\",\n      \"pmids\": [\"15082709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SUN2 specifically localizes to the nuclear envelope attachment sites of meiotic telomeres throughout their dynamic movement; EM reveals SUN2 is part of a membrane-spanning fibrillar complex interconnecting attached telomeres with cytoplasmic structures. This association does not require axial element assembly or A-type lamins.\",\n      \"method\": \"Immunofluorescence co-localization, electron microscopy, genetic ablation (lamin A-null, axial element-null mice)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal localization, ultrastructural EM, and genetic controls across multiple conditions in a single focused study\",\n      \"pmids\": [\"17452644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SUN1 and SUN2 function redundantly to retain Syne-1/Nesprin-1 at the nuclear envelope in skeletal muscle cells; loss of both SUN1 and SUN2 disrupts Syne-1 NE localization and causes defective myonuclear positioning (both synaptic and nonsynaptic), demonstrating a dosage-dependent genetic interaction.\",\n      \"method\": \"Sun1 and Sun2 single and double knockout mice, immunofluorescence for Syne-1 at NE, assessment of myonuclear positioning\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined phenotypic readouts, gene dosage series, and molecular marker analysis replicated across multiple allele combinations\",\n      \"pmids\": [\"19509342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"INM targeting of SUN2 requires three redundant elements: (1) a classical NLS (cNLS) in its N-terminal nucleoplasmic domain, (2) an adjacent arginine cluster that mediates coatomer-dependent Golgi retrieval, and (3) the C-terminal lumenal SUN domain, making SUN2 the first mammalian INM protein relying on a cNLS, Golgi retrieval signal, and perinuclear domain for targeting.\",\n      \"method\": \"Deletion/mutation constructs, live-cell fluorescence imaging, coatomer binding assays, pharmacological Golgi disruption\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — systematic mutagenesis combined with multiple functional localization assays and biochemical interaction studies in a single focused study\",\n      \"pmids\": [\"20551905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Lamin A (but not lamin C) is required for NE localization of SUN2; overexpression of Rab5 redistributes SUN2 to endosomes via its SUN domain; endogenous SUN2 co-localizes with Rab5 and overexpression of SUN2 stimulates transferrin uptake while SUN2 knockdown attenuates it, indicating a role in endocytosis.\",\n      \"method\": \"Lamin A/C-deficient cells rescued with lamin A or C, Rab5 overexpression/dominant-negative transfection, transferrin uptake assay, co-localization imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional rescue experiments and endocytosis assay, but single lab and limited mechanistic depth on the Rab5 interaction\",\n      \"pmids\": [\"21655223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SUN1 and SUN2 interact biochemically with the DNA-PK complex (Ku70/Ku80/DNA-PKcs) at the nuclear envelope; in Sun1/Sun2 double-knockout MEFs, activation of ATM and H2AX phosphorylation following DNA damage is impaired, and cells show premature S-phase arrest, increased apoptosis, and reduced perinuclear heterochromatin, placing SUN1/SUN2 upstream of DDR signaling.\",\n      \"method\": \"Sun1/Sun2 DKO mouse embryonic fibroblasts, biochemical co-immunoprecipitation screen, immunofluorescence for γH2AX/pATM, cell cycle FACS, DNAPK knockdown\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with phenotypic readout plus biochemical interaction, but interaction is from a screen and functional link to DNAPK is correlative\",\n      \"pmids\": [\"22863315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Accumulation of farnesylated prelamin A (as in mandibuloacral dysplasia type A) alters SUN2 distribution at the NE, causing a disorganized lattice; treatment with statins (farnesyltransferase inhibitors) partially rescues proper SUN2 organization, establishing that SUN2 localization depends on correctly processed lamin A.\",\n      \"method\": \"Patient-derived MADA fibroblasts, statin/FTI drug treatment, immunofluorescence for SUN2\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological rescue plus patient cell lines, but mechanism is indirect (lamin A processing affecting SUN2 localization) and not dissected further\",\n      \"pmids\": [\"22706480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SUN2 overexpression blocks HIV-1 infection between reverse transcription and nuclear entry in a capsid-specific manner; a single-amino-acid change in HIV capsid confers resistance; both HIV inhibition and nuclear shape deformation by SUN2 overexpression map to the nucleoplasmic/lamin-interacting domain of SUN2; cyclophilin A (CypA) is implicated in the SUN2-imposed block.\",\n      \"method\": \"Overexpression in cell lines and primary MDCs, passaging-selected capsid mutants, domain deletion mapping, chemical/genetic CypA inhibition, fluorescence imaging of nuclear shape\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (domain mapping, capsid mutant selection, CypA perturbation) in single lab\",\n      \"pmids\": [\"26865710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Endogenous SUN2 at the inner nuclear membrane is required for CypA-dependent positive effects of wild-type HIV on reverse transcription and nuclear import of viral cDNA in primary CD4+ T cells; CypA-resistant capsid mutants are not restricted by SUN2.\",\n      \"method\": \"SUN2 siRNA knockdown in primary CD4+ T cells, CypA inhibitor/knockdown, infection with wild-type and capsid mutant HIV-1/HIV-2/SIVmac\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological perturbation in primary cells with mechanistic dissection, single lab\",\n      \"pmids\": [\"27149839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SUN2 silencing in primary CD4+ T cells impairs their proliferative capacity, activation marker expression, and viability, and reduces viral protein expression in infected cells; the reduced HIV infection in SUN2-silenced CD4 T cells is independent of CypA.\",\n      \"method\": \"SUN2 siRNA in primary CD4+ T cells, proliferation assays, flow cytometry for activation markers, HIV infection assays with CypA inhibition\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary cell KD with multiple phenotypic readouts, CypA independence established; single lab\",\n      \"pmids\": [\"28077629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRISPR/Cas9-assembled CANC nanotubes captured both SUN1 and SUN2 from cell lysates, indicating physical interaction between HIV-1 capsid and SUN2; SUN2-/- CRISPR cells show a modest suppressive effect on HIV-1 infectivity.\",\n      \"method\": \"CRISPR/Cas9 knockout, in vitro capsid-nucleocapsid nanotube pulldown from cell lysates, HIV infectivity assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct pulldown assay plus genetic KO, but modest phenotype and single lab\",\n      \"pmids\": [\"28747499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SUN2 maintains repressive chromatin at the HIV-1 5'-LTR by associating with lamin A/C; lamin A/C tethers SUN2 to nucleosomes 1 and 2 of the HIV-1 5'-LTR, blocking RNA Pol II phosphorylation and recruitment; SUN2 knockdown converts LTR chromatin to an active state and reactivates HIV from latency; TNF-α-induced reactivation disrupts the SUN2–lamin A/C association.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), SUN2 knockdown/overexpression, HIV latency reactivation assays, RNA Pol II phosphorylation analysis\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, and functional latency assays, but single lab\",\n      \"pmids\": [\"29717016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Full-length SUN2 must trimerize (mediated by coiled-coil regions CC1 and CC2) to bind KASH-domain proteins; CC2-SUN alone forms an autoinhibited monomer; CC1–CC2 interplay releases autoinhibition; residue E452 on CC1 is involved in the monomer–trimer transition; Ca2+-dependent regulation of this transition is proposed.\",\n      \"method\": \"Molecular dynamics simulation (~1 µs), gel filtration analysis, mutagenesis of E452\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 (mutagenesis + gel filtration) / Moderate — computational model validated by gel filtration and mutagenesis, single lab; structural conclusion not from crystal structure\",\n      \"pmids\": [\"29995584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SUN2-null mice develop cardiac hypertrophy with enhanced AKT/MAPK signaling but without fibrosis or upregulation of pathological hypertrophy markers; in the absence of SUN2, MAN1 (a negative regulator of TGFβ signaling) accumulates at the NE, suppressing profibrotic TGFβ signaling, uncoupling hypertrophy from fibrosis.\",\n      \"method\": \"Sun2-/- mice, cardiac morphometry, Western blot for AKT/MAPK, MAN1 and TGFβ pathway markers, nuclear fractionation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotype and molecular pathway analysis, but mechanistic link to MAN1 is based on protein level changes without direct interaction proof; single lab\",\n      \"pmids\": [\"31091167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SUN2 is a component of the spliceosome complex (associated with SNRPD2, SNRPD3, NHP2L1-containing complex) and is required for efficient sororin (CDCA5) pre-mRNA splicing; SUN2 depletion increases sororin intron 1 retention, downregulates SMC1/MAU2/ESPL1, and inhibits TNBC cell proliferation via disruption of sister chromatid cohesion.\",\n      \"method\": \"Pulldown followed by mass spectrometry (protein–protein interaction), RNAi screen, RT-PCR for intron retention, FACS, western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-confirmed interaction plus functional splicing assay; single lab, novel finding for a nuclear membrane protein\",\n      \"pmids\": [\"33648524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Casein Kinase 2 (CK2) phosphorylates SUN2, enabling binding of the SCFβTrCP ubiquitin ligase which ubiquitinates SUN2; ubiquitinated SUN2 is then extracted from the membrane by the AAA ATPase p97 and delivered to the proteasome for degradation; the phosphatase CTDNEP1 opposes CK2 to stabilize SUN2. Accumulation of non-degradable SUN2 causes aberrant nuclear architecture, DNA damage vulnerability, and increased lagging chromosomes.\",\n      \"method\": \"In vitro kinase/ubiquitination assays, co-immunoprecipitation, phosphomimetic/non-degradable mutants, p97 inhibition, CTDNEP1 knockdown, nuclear morphology and mitosis assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of phosphorylation and ubiquitination, mutagenesis, multiple orthogonal cell biology readouts in a single rigorous study\",\n      \"pmids\": [\"36318477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXO2, an E3 ubiquitin ligase, recognizes glycosylated SUN2 and targets it for ubiquitin-proteasome-dependent degradation; this mechanism is driven upstream by transcription factor SOX6 promoting FBXO2 expression, defining a SOX6–FBXO2–SUN2 axis in ovarian cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, FBXO2 overexpression/knockdown, glycosylation analysis, TCGA/GEO data integration\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical ubiquitination assay and Co-IP; single lab with multiple methods\",\n      \"pmids\": [\"35525855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ECM rigidity upregulates SUN2 expression, and SUN2 in turn promotes metaphase-to-anaphase transition by facilitating mitotic spindle/astral microtubule organization; on soft ECM, low SUN2 levels perturb astral microtubule organization and delay anaphase onset.\",\n      \"method\": \"Polyacrylamide gels of defined stiffness, SUN2 knockdown/overexpression, live-cell mitosis imaging, microtubule organization analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined mechanical manipulation plus loss-of-function with specific mitotic phenotype, single lab\",\n      \"pmids\": [\"36322767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Conserved cysteines in the SUN domain undergo KASH-dependent inter- and intra-molecular disulfide bond rearrangements; disruption of the terminal disulfide bond compromises SUN2 localization, turnover, LINC complex assembly, cytoskeletal organization, and cell migration; ER lumen components regulate SUN2 cysteine redox state.\",\n      \"method\": \"Conformation-specific SUN2 antibody, biochemical disulfide-bond analysis, cysteine mutants, FRAP, cell migration assays, pharmacological/genetic ER redox perturbation\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of key cysteines combined with biochemical, imaging, and functional cell biology readouts in a single focused study\",\n      \"pmids\": [\"37188462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Aggregation of progerin at the NE triggers ER stress in a SUN2-dependent manner; the ability of SUN2 to cluster in the nuclear membrane is required for this ER stress induction, identifying SUN2 as a sensor/transducer of nucleoplasmic protein aggregates to the ER lumen.\",\n      \"method\": \"SUN2 knockdown/overexpression, SUN2 clustering mutants, ER stress reporter assays, live imaging in HGPS cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and domain-specific perturbation with functional ER stress readouts; single lab\",\n      \"pmids\": [\"37210724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SUN2 (but not SUN1) is required for Zika, dengue, and Japanese encephalitis virus replication; mechanistically, SUN2 facilitates cytoskeleton rearrangement and replication organelle formation by mediating the interaction between cytoskeletal actin and viral NS1; dominant-negative nesprin-1/2 (which connect SUN2 to cytoskeleton) reduces actin–NS1 interaction and viral replication.\",\n      \"method\": \"CRISPR/Cas9 SUN2 KO, co-immunoprecipitation of actin with NS1, dominant-negative nesprin constructs, viral RNA synthesis assays, neonatal mouse in vivo infection model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO plus biochemical interaction plus dominant-negative genetics plus in vivo mouse model; multiple orthogonal methods replicated across three viral species\",\n      \"pmids\": [\"38177122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Calcium elevations trigger rapid nuclear actin assembly requiring SUN2 independently of its LINC complex role; SUN2 co-localizes and associates with the formin/actin nucleator INF2 at the nuclear envelope in a calcium-regulated manner; SUN2 is required for active RNA Pol II clustering in response to calcium elevations.\",\n      \"method\": \"Calcium stimulation, SUN2 knockdown/knockout, co-immunoprecipitation of SUN2 with INF2, fluorescence imaging of nuclear actin and RNA Pol II clusters\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, genetic KD with specific functional readout (RNA Pol II clustering), single lab\",\n      \"pmids\": [\"39317734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Paclitaxel induces nuclear aberrations in interphase through SUN2-dependent disruption of lamin A/C levels and organization; SUN2 is required for lamin A/C reduction upon paclitaxel treatment and is regulated by polyubiquitylation; aberrant microtubule-vimentin bundles form during paclitaxel treatment coincident with SUN2-mediated nuclear deformation.\",\n      \"method\": \"Optical imaging, electron cryo-tomography, SUN2 knockdown/overexpression, lamin A/C quantification, ubiquitination assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cryo-ET structural imaging plus genetic KD and biochemical ubiquitination; single lab, novel finding\",\n      \"pmids\": [\"41367359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FRET-based nuclear tension sensors (NuTS2) placed across SUN2 measure tension forces transmitted through the LINC complex in living cells; NuTS2 reveals that force transmission across SUN2 increases with cell contractility and matrix stiffness, occurs dynamically during adhesion, migration, and nuclear squeeze, and shows a gradient increasing from posterior to anterior in zebrafish notochord cells as vacuoles expand.\",\n      \"method\": \"Genetically encoded FRET tension sensors inserted into SUN2, live-cell imaging, zebrafish notochord in vivo imaging, mechanical perturbations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biophysical measurement with FRET sensor in cells and in vivo; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.02.17.638756\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Sun2 is required for stiffness-dependent upregulation of ECM protein genes in lung fibroblasts; loss of Sun2 prevents lung fibrosis in bleomycin-treated mice without impairing myofibroblast formation or TGFβ responsiveness per se, indicating Sun2 acts as a mechanical coincidence detector for ECM gene induction.\",\n      \"method\": \"Sun2 knockout mice, bleomycin lung fibrosis model, substrate stiffness gels, gene expression profiling, TGFβ treatment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with defined fibrosis phenotype and mechanistic in vitro dissection; preprint, not peer-reviewed\",\n      \"pmids\": [\"41889916\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SUN2 mediates stiffness-dependent epigenetic remodeling in dermal fibroblasts; loss of Sun2 prevents bleomycin-induced skin fibrosis and abolishes stiffness-induced nuclear size changes and fibrotic gene expression; mechanistically, Sun2 is required for mechanical induction of the histone methyltransferase EZH2, defining three Sun2-dependent mechanosensitive chromatin states.\",\n      \"method\": \"Sun2 knockout mice, bleomycin skin fibrosis model, substrate stiffness gels, histone ChIP for H3K27me3, EZH2 western blot/knockdown, nuclear morphometry\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO plus chromatin-level mechanistic dissection; preprint, not peer-reviewed\",\n      \"pmids\": [\"41890082\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Farnesylated prelamin A variants reduce diffusional mobilities of nesprin-2 and SUN2 at the NE and impair their function in actin-driven nuclear rearward movement for cell polarization in a farnesylation-dependent manner; short C-terminal tail fragments of prelamin A variants are sufficient to disrupt polarity, identifying inhibition of the nesprin-2/SUN2 LINC complex as the common mechanism in prelamin A-related premature aging syndromes.\",\n      \"method\": \"FRAP for nesprin-2 and SUN2 mobility, cell polarization assays, expression of farnesylation-deficient prelamin A mutants, tail fragment expression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP plus domain-specific mutagenesis with functional polarization readout; single lab\",\n      \"pmids\": [\"42011117\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SUN2 is an integral inner nuclear membrane protein whose N-terminal nucleoplasmic cNLS, coatomer-retrieval signal, and lumenal SUN domain collectively target it to the INM, where it forms trimers (regulated by CC1–CC2 coiled-coil interplay and disulfide bond rearrangements in the SUN domain) to bind KASH-domain nesprins and thereby bridge the nucleoskeleton to the cytoskeleton; its stability is controlled by CK2-mediated phosphorylation triggering SCFβTrCP ubiquitination and p97-dependent proteasomal degradation (opposed by CTDNEP1), as well as by FBXO2-mediated recognition of glycosylated SUN2; through these LINC interactions SUN2 (i) positions nuclei in skeletal muscle by retaining Syne-1/Nesprin-1 at the NE, (ii) transmits mechanical forces from ECM stiffness to drive mitotic spindle organization, fibrotic gene programs (via EZH2/chromatin), and endothelial homeostasis, (iii) tethers meiotic telomeres to the NE for bouquet formation, (iv) supports DNA-damage responses by interacting with the DNA-PK complex, (v) associates with INF2 at the NE in a calcium-regulated manner to promote nuclear actin polymerization and RNA Pol II clustering, (vi) modulates HIV infection at the nuclear envelope through capsid/CypA-dependent and lamin A/C–chromatin-dependent mechanisms, and (vii) facilitates flavivirus replication by mediating NS1–actin cytoskeletal interactions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SUN2 is an integral inner nuclear membrane (INM) protein that forms the nucleoplasmic half of the LINC complex, physically coupling the nucleoskeleton to the cytoskeleton and serving as a node for mechanotransduction, nuclear positioning, and genome organization [#0, #2]. It localizes to the INM through three redundant signals\\u2014an N-terminal classical NLS, an adjacent coatomer-dependent Golgi-retrieval arginine cluster, and the C-terminal lumenal SUN domain\\u2014and its NE retention further depends on correctly processed lamin A [#3, #4]. Functional LINC assembly requires SUN2 to convert from an autoinhibited monomer to a CC1/CC2 coiled-coil-stabilized trimer competent to bind KASH-domain nesprins, a transition reinforced by KASH-dependent disulfide-bond rearrangements among conserved SUN-domain cysteines whose redox state is set by the ER lumen [#12, #18]. Through these nesprin connections SUN2 retains Syne-1/Nesprin-1 at the muscle NE to position myonuclei and tethers meiotic telomeres to the envelope for their dynamic movement [#1, #2]. SUN2 transmits mechanical force from ECM stiffness across the NE, driving mitotic spindle and astral-microtubule organization, stiffness-dependent fibrotic gene programs via EZH2-mediated chromatin remodeling, and direct LINC tension measurable in living cells [#17, #23, #25]. SUN2 also gates genome function and stress responses\\u2014supporting DNA-damage signaling via the DNA-PK complex, associating with the actin nucleator INF2 to drive calcium-triggered nuclear actin assembly and RNA Pol II clustering, and participating in pre-mRNA splicing of sororin [#5, #21, #14]. SUN2 abundance is tightly controlled by CK2 phosphorylation that licenses SCF\\u03b2TrCP ubiquitination and p97-dependent proteasomal extraction, opposed by the phosphatase CTDNEP1, and by FBXO2-mediated recognition of glycosylated SUN2 [#15, #16]. In viral infection SUN2 both restricts and supports HIV-1 at the nuclear envelope through capsid/CypA- and lamin A/C\\u2013chromatin-dependent mechanisms and is required for flavivirus replication by bridging actin to viral NS1 [#7, #11, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that SUN2 is an INM protein with its SUN domain in the perinuclear lumen, defining the topology required for any nucleoskeleton-cytoskeleton bridging function.\",\n      \"evidence\": \"Tagged deletion constructs, fractionation, EM, and marker co-localization in mammalian cells\",\n      \"pmids\": [\"15082709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding partners on either membrane face not yet identified\", \"No functional readout of LINC bridging\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed SUN2 marks NE attachment sites of meiotic telomeres within a membrane-spanning fibrillar complex, the first concrete role linking SUN2 to coupling nuclear contents to cytoplasmic structures.\",\n      \"evidence\": \"Immunofluorescence, EM, and lamin A-null / axial element-null mouse genetics\",\n      \"pmids\": [\"17452644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic partner mediating telomere movement not defined\", \"Whether SUN2 is essential versus redundant for bouquet formation unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated SUN1/SUN2 functional redundancy in retaining nesprin at the NE and positioning myonuclei, establishing the genetic logic of LINC dosage in tissue.\",\n      \"evidence\": \"Sun1/Sun2 single and double knockout mice with nesprin localization and myonuclear positioning readouts\",\n      \"pmids\": [\"19509342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SUN2\\u2013Syne-1 interaction interface not mapped here\", \"Tissue specificity of redundancy unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Answered how SUN2 reaches the INM, revealing reliance on a cNLS, a coatomer-retrieval signal, and the SUN domain together.\",\n      \"evidence\": \"Systematic mutagenesis, live imaging, coatomer-binding and Golgi-disruption assays\",\n      \"pmids\": [\"20551905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative weight of each signal in physiological context not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked SUN2 NE retention to lamin A and implicated SUN2 in endocytic transferrin uptake via Rab5, broadening its localization dependencies and possible roles.\",\n      \"evidence\": \"Lamin A/C rescue, Rab5 perturbation, and transferrin uptake assays\",\n      \"pmids\": [\"21655223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of SUN2\\u2013Rab5 endocytic role shallow\", \"Single lab; physiological relevance of endosomal pool unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed SUN1/SUN2 upstream of DNA-damage signaling through physical association with the DNA-PK complex and DDR phenotypes in DKO cells.\",\n      \"evidence\": \"Sun1/Sun2 DKO MEFs, Co-IP screen, \\u03b3H2AX/pATM imaging, DNAPK knockdown\",\n      \"pmids\": [\"22863315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction from a screen; reciprocal validation limited\", \"Functional link to DNAPK correlative\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined SUN2 as a modulator of HIV-1 at the nuclear envelope, with capsid/CypA-dependent restriction mapping to its lamin-interacting nucleoplasmic domain and an opposing endogenous requirement for productive infection.\",\n      \"evidence\": \"Overexpression and knockdown in cell lines and primary CD4+ T cells, capsid mutant selection, CypA perturbation\",\n      \"pmids\": [\"26865710\", \"27149839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dual restrictive/supportive role mechanistically unreconciled\", \"Direct capsid contact not shown in these studies\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed direct physical capture of SUN2 by HIV-1 capsid and that SUN2 also supports CD4+ T-cell proliferation and viability, complicating its net effect on infection.\",\n      \"evidence\": \"CRISPR knockout, CANC nanotube pulldown, proliferation/activation assays\",\n      \"pmids\": [\"28747499\", \"28077629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phenotypes modest\", \"Whether T-cell fitness effect confounds infection readouts\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a chromatin-level role: SUN2 with lamin A/C tethers and silences the HIV-1 5'-LTR, blocking RNA Pol II recruitment and enforcing latency.\",\n      \"evidence\": \"Co-IP, ChIP, knockdown/overexpression, latency reactivation assays\",\n      \"pmids\": [\"29717016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalization beyond LTR to host genes untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the structural logic of LINC assembly, showing trimerization driven by CC1/CC2 interplay relieves SUN-domain autoinhibition to enable KASH binding.\",\n      \"evidence\": \"Molecular dynamics simulation, gel filtration, E452 mutagenesis\",\n      \"pmids\": [\"29995584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal structure of full-length trimer\", \"Proposed Ca2+ regulation not directly demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered an unexpected spliceosome-associated function, with SUN2 required for sororin pre-mRNA splicing and sister chromatid cohesion in cancer cells.\",\n      \"evidence\": \"Pulldown-MS, RNAi, intron-retention RT-PCR, FACS in TNBC cells\",\n      \"pmids\": [\"33648524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How an INM protein engages the spliceosome unexplained\", \"Single lab; cancer-specific context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the proteostatic control of SUN2: a CK2\\u2013SCF\\u03b2TrCP\\u2013p97 degradation axis opposed by CTDNEP1, with a parallel FBXO2/SOX6 route for glycosylated SUN2.\",\n      \"evidence\": \"In vitro kinase/ubiquitination reconstitution, degron mutants, p97 inhibition, CTDNEP1 knockdown; separate FBXO2 Co-IP and ubiquitination assays\",\n      \"pmids\": [\"36318477\", \"35525855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for CK2 phosphorylation in vivo unclear\", \"Crosstalk between the two degradation routes unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected SUN2 to mechanically driven mitosis, with ECM stiffness raising SUN2 to organize astral microtubules and license anaphase onset.\",\n      \"evidence\": \"Defined-stiffness gels, SUN2 knockdown/overexpression, live mitosis imaging\",\n      \"pmids\": [\"36322767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link from SUN2 to spindle apparatus not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established redox control of SUN2, with KASH-dependent disulfide rearrangements governing localization, turnover, LINC assembly, and migration.\",\n      \"evidence\": \"Conformation-specific antibody, cysteine mutants, FRAP, migration assays, ER redox perturbation\",\n      \"pmids\": [\"37188462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ER lumenal oxidoreductase responsible not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified SUN2 as a transducer of nucleoplasmic protein aggregation to the ER, with its clustering required for progerin-triggered ER stress.\",\n      \"evidence\": \"Knockdown/overexpression, clustering mutants, ER stress reporters in HGPS cells\",\n      \"pmids\": [\"37210724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal relayed across membrane to ER lumen undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed SUN2-specific support of flavivirus replication by bridging cytoskeletal actin to viral NS1 for replication organelle formation.\",\n      \"evidence\": \"CRISPR KO, actin\\u2013NS1 Co-IP, dominant-negative nesprin, viral RNA assays, neonatal mouse model across three viruses\",\n      \"pmids\": [\"38177122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SUN2 directly contacts NS1 versus via actin unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a LINC-independent role for SUN2 in calcium-triggered nuclear actin assembly via INF2, coupling calcium signaling to RNA Pol II clustering.\",\n      \"evidence\": \"Calcium stimulation, knockdown/knockout, SUN2\\u2013INF2 Co-IP, nuclear actin and Pol II imaging\",\n      \"pmids\": [\"39317734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How INM SUN2 nucleates nucleoplasmic actin geometrically unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Directly measured LINC tension across SUN2 in living cells, showing force transmission scales with contractility and stiffness and varies spatially in vivo.\",\n      \"evidence\": \"FRET tension sensors inserted into SUN2, live-cell and zebrafish notochord imaging (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.02.17.638756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Sensor insertion effects on native function not fully controlled\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined SUN2 as a mechanical coincidence detector driving stiffness-dependent fibrotic gene programs through EZH2/H3K27me3 chromatin remodeling, with loss preventing organ fibrosis in vivo.\",\n      \"evidence\": \"Sun2 knockout mice, bleomycin lung and skin fibrosis models, stiffness gels, EZH2/H3K27me3 ChIP and expression profiling (preprints)\",\n      \"pmids\": [\"41889916\", \"41890082\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprints, not peer-reviewed\", \"Path from LINC tension to EZH2 induction not molecularly traced\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected SUN2 mobility defects to laminopathy mechanism, with farnesylated prelamin A immobilizing the nesprin-2/SUN2 LINC complex to impair actin-driven nuclear positioning and cell polarization.\",\n      \"evidence\": \"FRAP of nesprin-2 and SUN2, farnesylation-deficient prelamin A and tail-fragment expression, polarization assays\",\n      \"pmids\": [\"42011117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct prelamin A\\u2013SUN2 contact versus indirect lamina effect not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SUN2's diverse roles\\u2014LINC bridging, mechanosensing-to-chromatin signaling, splicing, nuclear actin, and viral modulation\\u2014are coordinated within a single protein, and how force across the SUN domain is converted into transcriptional and chromatin outputs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking mechanical input to chromatin/transcriptional output\", \"Structural basis of force transmission through trimeric SUN2 unsolved\", \"Reconciliation of restrictive versus supportive viral roles missing\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 12, 18]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [17, 19, 23]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [20, 21]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [18, 19]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [11, 25]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [14, 17]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [20, 24, 25]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [19, 23]}\n    ],\n    \"complexes\": [\"LINC complex\", \"spliceosome\"],\n    \"partners\": [\"SYNE1\", \"SYNE2\", \"LMNA\", \"INF2\", \"FBXO2\", \"CTDNEP1\", \"PRKDC\", \"VCP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}