- Length
- 889 aa
- Mass
- 97.7 kDa
- Annotated
- 2026-04-29
55 papers in source corpus
20 papers cited in narrative
20 extracted findings
Mechanistic narrative
Synthesis pass · prose summary of the discoveries below
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Mechanism profile
Synthesis pass · controlled-vocabulary classification · explore literature graph →
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Evidence
Reading pass · 20 per-paper findings extracted from the source corpus
| Year | Finding | Method | Journal | Conf | PMIDs |
|---|---|---|---|---|---|
| 2005 | PACS-2 controls the apposition of mitochondria with the ER; depletion of PACS-2 causes BAP31-dependent mitochondria fragmentation and uncoupling from the ER. PACS-2 also translocates Bid to mitochondria in response to apoptotic inducers, triggering truncated Bid formation, cytochrome c release, and caspase-3 activation. | siRNA knockdown, subcellular fractionation, fluorescence microscopy, co-immunoprecipitation, cell death assays | The EMBO journal | High | 15692567 |
| 2008 | PACS-2 interacts with calnexin's cytosolic domain to sort calnexin between the rough ER, mitochondria-associated membrane (MAM), and plasma membrane. Phosphorylation of calnexin Ser554/564 by CK2 reduces its binding to PACS-2, redirecting calnexin to the cell surface. | siRNA knockdown, co-immunoprecipitation, phosphomimetic mutagenesis, immunofluorescence, flow cytometry | Molecular biology of the cell | High | 18417615 |
| 2008 | HIV-1 Nef binds PACS-2 via Nef EEEE65, which targets Nef to the paranuclear/TGN region, enabling PXXP75 to activate a TGN-localized Src family kinase (SFK)–ZAP70–PI3K cascade required for MHC-I down-regulation. Genetic loss of PACS-2 (Pacs-2−/− splenocytes and fibroblasts) prevents Nef paranuclear localization and MHC-I internalization. | Co-immunoprecipitation, siRNA knockdown, Pacs-2 knockout mouse cells, fluorescence microscopy, kinase assays | The Journal of biological chemistry | High | 18296443 |
| 2009 | PACS-2 is phosphorylated at Ser437 in vivo by Akt; phospho-Ser437 binds 14-3-3 with high affinity, which represses PACS-2 apoptotic activity while maintaining its membrane-trafficking function. TRAIL triggers Ser437 dephosphorylation, switching PACS-2 from a homeostatic to a pro-apoptotic state. | In vivo phosphorylation mapping, pharmacological Akt inhibition, genetic Akt studies, 14-3-3 co-immunoprecipitation, TRAIL cytotoxicity assays, mouse hepatocyte infection model | Molecular cell | High | 19481529 |
| 2012 | PACS-2 and PACS-1 interact with Nef via a bipartite site formed by Nef EEEE65 (N-terminal domain) and W113 (core domain) binding to a cargo subsite on PACS-1/PACS-2. This interaction occurs on Rab5- and Rab7-positive endosomes (visualized by bimolecular fluorescence complementation) and is required for Nef-induced MHC-I down-regulation. | Bimolecular fluorescence complementation, co-immunoprecipitation, site-directed mutagenesis, MHC-I surface assay in PBMCs | Molecular biology of the cell | High | 22496420 |
| 2012 | TRAIL induces recruitment of PACS-2 to DR5-positive endosomes where it forms a complex with Bim and Bax on lysosomal membranes, promoting lysosomal membrane permeabilization and cathepsin B release. In vitro, recombinant PACS-2 binds Bim directly but not Bax; Bim is required for subsequent Bax recruitment. | shRNA knockdown, co-immunoprecipitation, in vitro binding assay with recombinant proteins, lysosomal membrane permeabilization assay, clonogenic survival | The Journal of biological chemistry | High | 22645134 |
| 2014 | PACS-2 shuttles from the cytoplasm to the nucleus where it interacts with SIRT1 and directly inhibits SIRT1-catalyzed p53 deacetylation, thereby sustaining p53 acetylation and p21 induction required for DNA-damage-induced cell-cycle arrest. Pacs-2−/− thymocytes show reduced p53 acetylation and blunted p21 induction. | In vitro SIRT1 deacetylation assay, co-immunoprecipitation, Pacs-2 knockout mouse thymocytes, SIRT1 inhibitor rescue, subcellular fractionation | Cell reports | High | 25159152 |
| 2014 | cIAP-1 and cIAP-2 directly bind PACS-2 and mediate K48-linked poly-ubiquitination of PACS-2, targeting it for proteasomal degradation. Dual cIAP knockout reduces PACS-2 ubiquitination, elevates PACS-2 levels, and sensitizes cells to TRAIL-induced lysosomal membrane permeabilization in a PACS-2-dependent manner. | Cell-free ubiquitination assay, co-immunoprecipitation, single and double c-Iap knockout mouse hepatocytes, cycloheximide chase | PloS one | High | 24633224 |
| 2015 | PACS-2 co-localizes with ADAM17 on early endosomes and is required for recycling of internalized ADAM17 away from degradative pathways back to the cell surface. PACS-2 loss reduces ADAM17 cell-surface levels, ADAM17-dependent ErbB ligand shedding, and EGFR signaling; Pacs2−/− mice show reduced phospho-EGFR and intestinal proliferation. | Genome-wide siRNA screen, confocal co-localization, ADAM17 recycling assay, Pacs2 knockout mice, EGFR phosphorylation assay | Nature communications | High | 26108729 |
| 2016 | Cytoplasmic PACS-2 interacts with ATM to drive NF-κB activation and induction of anti-apoptotic Bcl-xL following DNA damage. Pacs-2−/− thymocytes show blunted Bcl-xL induction, increased mitochondrial outer membrane permeabilization, and accelerated apoptosis after genotoxic stress; PACS-2 is not required for TNFα-induced NF-κB activation. | Co-immunoprecipitation, Pacs-2 knockout mouse thymocytes, mitochondrial membrane permeabilization assay, NF-κB reporter, western blot | Cell death and differentiation | High | 26943323 |
| 2018 | PACS-2 engages an insulin-responsive sensor in the SIRT1 N-terminal disordered region comprising an acidic cluster (AC) and a 3-helix bundle (3HB). DBC1 removes a distal shield from the 3HB, permitting PACS-2 to engage the AC and transiently exposed helix 3, disrupting 3HB structure and inhibiting SIRT1 catalysis. The SIRT1 activator SRT1720 stabilizes the 3HB and protects SIRT1 from PACS-2-mediated inhibition. | NMR structural analysis, in vitro SIRT1 deacetylation assay, co-immunoprecipitation, mutagenesis, STAC binding assay | Molecular cell | High | 30415949 |
| 2018 | The recurrent PACS-2 E209K missense variant reduces the ability of the autoregulatory domain to modulate the interaction between the PACS-2 FBR (cargo-binding region) and client proteins, potentially disturbing cellular trafficking and causing developmental epileptic encephalopathy. | Functional binding assay comparing WT and E209K FBR-client interactions, whole-exome sequencing in 14 individuals | American journal of human genetics | Medium | 29656858 |
| 2019 | PACS-2 knockdown impairs mitophagosome formation and mitophagy in vascular smooth muscle cells; increased MAM contacts and PACS-2-associated MAMs are observed upon atherogenic lipid stimulation, and disrupting MAMs via PACS-2 loss potentiates VSMC apoptosis. | High-resolution confocal microscopy, proximity ligation assay, siRNA knockdown, mitophagy flux assay, apoptosis assay | Cells | Medium | 31242668 |
| 2019 | PACS2 promotes MAM formation and mitochondrial Ca2+ transfer in endothelial cells; ox-LDL increases PACS2 localization at mitochondria and ER-mitochondria contacts, and silencing PACS2 inhibits ox-LDL-induced mitochondrial Ca2+ elevation, ROS production, MMP loss, cytochrome c release, and apoptosis. | siRNA knockdown, confocal microscopy of MAM contacts, mitochondrial Ca2+ measurement, ROS/MMP/cytochrome c assays | Experimental cell research | Medium | 30970236 |
| 2022 | PACS-2 interacts with BECN1 (Beclin-1) and mediates its relocalization to MAM, where BECN1 promotes mitophagosome formation. PACS-2 overexpression blocks mitochondrial DRP1 recruitment, reducing excessive mitochondrial fission and restoring mitophagy in high-glucose conditions. | Co-immunoprecipitation, proximity ligation assay, confocal microscopy, conditional Pacs-2 knockout mice, PACS-2 overexpression in HK-2 cells, mitophagy flux assay | Diabetes | High | 35133431 |
| 2022 | PACS2 interacts with TRPV1; reduced PACS2 levels during ER stress are influenced by this interaction, and restoration of PACS2 via TRPV1-modulating drug capsaicin reduces ER-mitochondria uncoupling and alveolar epithelial apoptosis in IPF models. | Co-immunoprecipitation, confocal microscopy, overexpression/knockdown in AEC2 cells, precision-cut lung slices from IPF patients, apoptosis assay | Cellular and molecular life sciences | Medium | 35212819 |
| 2022 | PACS-2 E209K mutation increases the protein's half-life (slower turnover), increases association with 14-3-3ε, and increases susceptibility to staurosporine-induced apoptosis compared to wild-type PACS-2. | Cycloheximide chase, co-immunoprecipitation, staurosporine apoptosis assay in HCT116 cells | ACS omega | Medium | 36188273 |
| 2023 | PACS-2 interacts with transcription factor EB (TFEB) and promotes its nuclear translocation, which activates expression of the ER-phagy receptor FAM134B, thereby facilitating ER-phagy in renal tubular cells. | Co-immunoprecipitation, nuclear fractionation, PACS-2 overexpression and siRNA knockdown, FAM134B siRNA rescue, Pacs-2 proximal tubule-specific KO mice | Cell death & disease | Medium | 37794057 |
| 2024 | PACS-2 suppresses phosphorylation and nuclear translocation of SP1, thereby downregulating LRRK2 expression. Reduced LRRK2 decreases ubiquitination and degradation of Mfn2 via the JNK pathway, preserving MAM integrity and nucleus pulposus stem cell survival. | Co-immunoprecipitation, western blot, Pacs-2 knockout mice, overexpression studies, ubiquitination assay | Advanced science | Medium | 41190767 |
| 2024 | PACS-2 is required for CCHFV glycoprotein (Gn and Gc) trafficking through the retrograde network; loss of PACS-2 impairs CCHFV assembly and release of infectious viral particles. | Infection assays, biochemical trafficking assays, confocal microscopy in virus-producing cells, siRNA knockdown | Emerging microbes & infections | Medium | 38661085 |
Source papers
Stage 0 corpus · 55 papers · ranked by NIH iCite citations
| Year | Title | Journal | Citations | PMID |
|---|---|---|---|---|
| 2005 | PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. | The EMBO journal | 492 | 15692567 |
| 2008 | The subcellular distribution of calnexin is mediated by PACS-2. | Molecular biology of the cell | 188 | 18417615 |
| 2014 | miR-499 protects cardiomyocytes from H 2O 2-induced apoptosis via its effects on Pdcd4 and Pacs2. | RNA biology | 108 | 24646523 |
| 2022 | PACS-2 Ameliorates Tubular Injury by Facilitating Endoplasmic Reticulum-Mitochondria Contact and Mitophagy in Diabetic Nephropathy. | Diabetes | 81 | 35133431 |
| 2019 | The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites. | Cells | 75 | 31242668 |
| 2020 | PACS-2: A key regulator of mitochondria-associated membranes (MAMs). | Pharmacological research | 74 | 32673704 |
| 2008 | HIV-1 Nef binds PACS-2 to assemble a multikinase cascade that triggers major histocompatibility complex class I (MHC-I) down-regulation: analysis using short interfering RNA and knock-out mice. | The Journal of biological chemistry | 73 | 18296443 |
| 2014 | The multifunctional sorting protein PACS-2 regulates SIRT1-mediated deacetylation of p53 to modulate p21-dependent cell-cycle arrest. | Cell reports | 69 | 25159152 |
| 2009 | Akt and 14-3-3 control a PACS-2 homeostatic switch that integrates membrane traffic with TRAIL-induced apoptosis. | Molecular cell | 66 | 19481529 |
| 2001 | Effect of postoperative atrial fibrillation on length of stay after cardiac surgery (The Postoperative Atrial Fibrillation in Cardiac Surgery study [PACS(2)]. | The American journal of cardiology | 65 | 11274944 |
| 2019 | PACS2 is required for ox-LDL-induced endothelial cell apoptosis by regulating mitochondria-associated ER membrane formation and mitochondrial Ca2+ elevation. | Experimental cell research | 58 | 30970236 |
| 2018 | A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis. | American journal of human genetics | 57 | 29656858 |
| 2012 | An interdomain binding site on HIV-1 Nef interacts with PACS-1 and PACS-2 on endosomes to down-regulate MHC-I. | Molecular biology of the cell | 57 | 22496420 |
| 2021 | PACS-2 attenuates diabetic kidney disease via the enhancement of mitochondria-associated endoplasmic reticulum membrane formation. | Cell death & disease | 52 | 34836936 |
| 2012 | Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein-induced lysosomal translocation of proapoptotic effectors is mediated by phosphofurin acidic cluster sorting protein-2 (PACS-2). | The Journal of biological chemistry | 47 | 22645134 |
| 2015 | The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17. | Nature communications | 45 | 26108729 |
| 2018 | An Insulin-Responsive Sensor in the SIRT1 Disordered Region Binds DBC1 and PACS-2 to Control Enzyme Activity. | Molecular cell | 41 | 30415949 |
| 2016 | PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage. | Cell death and differentiation | 30 | 26943323 |
| 2024 | PACS2/CPT1A/DHODH signaling promotes cardiomyocyte ferroptosis in diabetic cardiomyopathy. | Cardiovascular diabetology | 29 | 39633391 |
| 2022 | Ferulic acid attenuates high glucose-induced MAM alterations via PACS2/IP3R2/FUNDC1/VDAC1 pathway activating proapoptotic proteins and ameliorates cardiomyopathy in diabetic rats. | International journal of cardiology | 27 | 36481261 |
| 2014 | Cellular inhibitor of apoptosis (cIAP)-mediated ubiquitination of phosphofurin acidic cluster sorting protein 2 (PACS-2) negatively regulates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity. | PloS one | 27 | 24633224 |
| 2022 | PACS2-TRPV1 axis is required for ER-mitochondrial tethering during ER stress and lung fibrosis. | Cellular and molecular life sciences : CMLS | 25 | 35212819 |
| 2022 | PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease. | Molecular medicine (Cambridge, Mass.) | 25 | 36138342 |
| 2023 | PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy. | Cell death & disease | 22 | 37794057 |
| 2019 | Expanding the clinical spectrum associated with PACS2 mutations. | Clinical genetics | 19 | 30684285 |
| 2022 | AKT/PACS2 Participates in Renal Vascular Hyperpermeability by Regulating Endothelial Fatty Acid Oxidation in Diabetic Mice. | Frontiers in pharmacology | 13 | 35865947 |
| 2023 | Mitochondria-associated membrane protein PACS2 maintains right cardiac function in hypobaric hypoxia. | iScience | 11 | 36968068 |
| 2020 | Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis. | American journal of medical genetics. Part A | 11 | 33369122 |
| 2024 | Renal denervation improves mitochondrial oxidative stress and cardiac hypertrophy through inactivating SP1/BACH1-PACS2 signaling. | International immunopharmacology | 9 | 39173402 |
| 2022 | The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis. | ACS omega | 9 | 36188273 |
| 2022 | First reported case of an inherited PACS2 pathogenic variant with variable expression. | Epileptic disorders : international epilepsy journal with videotape | 7 | 35770754 |
| 2019 | MAP‑1B, PACS‑2 and AHCYL1 are regulated by miR‑34A/B/C and miR‑449 in neuroplasticity following traumatic spinal cord injury in rats: Preliminary explorative results from microarray data. | Molecular medicine reports | 7 | 31432119 |
| 2021 | [Early infantile epileptic encephalopathy caused by PACS2 gene variation: three cases report and literature review]. | Zhonghua er ke za zhi = Chinese journal of pediatrics | 6 | 34405643 |
| 2025 | PACS2 initiates foam cell formation in macrophages through the ROS-PPARγ-CD36 positive feedback loop. | Biochemical pharmacology | 5 | 40653022 |
| 2022 | Knockdown of circ_0002194 protects against oxidized low-density lipoprotein-induced cell damage via the regulation of the miR-637/PACS2 axis in human vascular endothelial cells. | Interactive cardiovascular and thoracic surgery | 5 | 35951762 |
| 2017 | Loss of PACS-2 delays regeneration in DSS-induced colitis but does not affect the ApcMin model of colorectal cancer. | Oncotarget | 5 | 29312533 |
| 2024 | PACS-1 variant protein is aberrantly localized in Caenorhabditis elegans model of PACS1/PACS2 syndromes. | Genetics | 4 | 39031646 |
| 2021 | Vein of Galen aneurysm, dilated cardiomyopathy, and slender habitus in a patient with a recurrent pathogenic variant in PACS2. | American journal of medical genetics. Part A | 4 | 34894068 |
| 2025 | PACS2/PKCα/NOX4 pathway damaged the renal vascular endothelial barrier by promoting ROS production in diabetic nephropathy mice. | Molecular and cellular biochemistry | 3 | 40775117 |
| 2023 | Long-Term Outcome of Neonatal Seizure with PACS2 Mutation: Case Series and Literature Review. | Children (Basel, Switzerland) | 3 | 37189870 |
| 2022 | First Report of Mexican Patients with PACS1-Related Neurodevelopmental Disorder and Review of the PACS1-, PACS2-, and WDR37-Related Ophthalmological Manifestations. | Molecular syndromology | 2 | 37064331 |
| 2025 | AI-Based Facial Phenotyping Supports a Shared Molecular Axis in PACS1-, PACS2-, and WDR37-Related Syndromes. | International journal of molecular sciences | 1 | 40869285 |
| 2025 | PACS-2 Mitigates NPSC Apoptosis and Intervertebral Disc Degeneration by Preserving MAM Integrity via the SP1/LRRK2/Mfn2 Axis. | Advanced science (Weinheim, Baden-Wurttemberg, Germany) | 1 | 41190767 |
| 2024 | A missense variant in the PACS2 gene cause Epileptic Encephalopathy and seizures in Saudi family. | Pakistan journal of medical sciences | 1 | 38545008 |
| 2024 | PACS2, PACS1, and VACTERL: A Clinical Overlap. | Molecular syndromology | 1 | 39911171 |
| 2023 | PACS2 pathogenic variant associated with malformation of cortical development and epilepsy. | Epileptic disorders : international epilepsy journal with videotape | 1 | 38031819 |
| 2021 | [Clinical and genetic analysis of PACS2 gene variant in two child patients with developmental and epileptic encephalopathy 66]. | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 1 | 34625934 |
| 2026 | MiR-499-5P/PACS2/TRPV1 Axis Maintains Mitochondrial Homeostasis and Left Ventricular Function after Extreme Cold Stress. | Journal of cardiovascular translational research | 0 | 41644764 |
| 2026 | PACS2 deficiency ameliorates hepatic steatosis via inhibition of the JNK signaling pathway in diabetic mice. | Biochemical pharmacology | 0 | 41687826 |
| 2026 | Quercetin Alleviates Endothelial Dysfunction in Atherosclerosis by Inhibiting Ferroptosis Through PACS2/HMOX-1 Pathway. | The American journal of Chinese medicine | 0 | 41692703 |
| 2026 | Crebanine attenuates copper neurotoxicity via PACS-2 upregulation and TXNIP/TRPV1 axis suppression. | Neurotoxicology | 0 | 41962777 |
| 2024 | Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature. | Biomolecules | 0 | 38540691 |
| 2024 | The PACS-2 protein and trafficking motifs in CCHFV Gn and Gc cytoplasmic domains govern CCHFV assembly. | Emerging microbes & infections | 0 | 38661085 |
| 2024 | PACS-1 variant protein is aberrantly localized in C. elegans model of PACS1/PACS2 syndromes. | bioRxiv : the preprint server for biology | 0 | 38712144 |
| 2024 | Understanding PACS2 syndrome's pathomechanism by studying E209K and E211K mutations. | Mammalian genome : official journal of the International Mammalian Genome Society | 0 | 39738582 |