{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPhosphofurin acidic cluster sorting protein‐2 (PACS2) is a multifunctional sorting adaptor that orchestrates intracellular membrane dynamics by regulating the juxtaposition and communication between the endoplasmic reticulum (ER) and mitochondria. PACS2 governs the formation of mitochondria‐associated membranes (MAMs), which serve as platforms for lipid synthesis, calcium exchange, and chaperone distribution – for example, it modulates the localization of calnexin within distinct ER domains. Moreover, PACS2 directs the trafficking of key membrane proteins such as polycystin‐2 by recognizing phosphorylated acidic cluster motifs, and it even intercedes in the regulation of metabolic enzymes, as seen in its role in modulating the conformation and activity of SIRT1 in response to insulin signaling and cellular stress."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its trafficking functions, PACS2 is a central regulator of cell fate via its control of apoptotic and immune‐modulatory pathways. It is recruited in response to death receptor signals – for instance, in TRAIL‐mediated apoptosis PACS2 helps assemble critical kinase cascades and mediates lysosomal membrane permeabilization by recruiting proapoptotic factors such as Bid and Bax. PACS2 is also co‐opted by viral proteins like HIV‐1 Nef, which binds PACS2 to misroute host MHC‐I molecules and thereby facilitate immune evasion. Regulation of PACS2 levels via ubiquitination by cIAP proteins further highlights its role as a finely tuned molecular switch balancing cellular homeostasis and programmed cell death."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging genetic evidence has linked PACS2 dysfunction to neurodevelopmental disorders, notably developmental and epileptic encephalopathies characterized by neonatal seizure onset, cerebellar dysgenesis, distinct facial dysmorphism, and intellectual disability. Spatial clustering analyses of de novo mutations have identified recurrent missense changes in PACS2 that disrupt its autoregulatory functions, suggesting that alteration in PACS2‐mediated sorting and organelle communication may underlie these complex syndromes. Collectively, these studies underscore PACS2’s central role in both cellular homeostasis and organismal development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Thomas Simmen, Joseph E Aslan, Anastassia D Blagoveshchenskaya, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.emboj.7600566"}], "href": "https://doi.org/10.1038/sj.emboj.7600566"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15692563"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15692563"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Nathan Myhill, Emily M Lynes, Jalal A Nanji, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "An Insulin-Responsive Sensor in the SIRT1 Disordered Region Binds DBC1 and PACS-2 to Control Enzyme Activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2018.10.007"}], "href": "https://doi.org/10.1016/j.molcel.2018.10.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30415949"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30415949"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Manon Moulis, Elisa Grousset, Julien Faccini, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "MAPK1 Mediates MAM Disruption and Mitochondrial Dysfunction in Diabetic Kidney Disease via the PACS-2-Dependent Mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biol Sci (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7150/ijbs.89291"}], "href": "https://doi.org/10.7150/ijbs.89291"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38169625"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38169625"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Katelyn M Atkins, Laurel Thomas, Robert T Youker, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Akt and 14-3-3 control a PACS-2 homeostatic switch that integrates membrane traffic with TRAIL-induced apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2009.04.011"}], "href": "https://doi.org/10.1016/j.molcel.2009.04.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19481529"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19481529"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Jimmy D Dikeakos, Laurel Thomas, Grace Kwon, et al. 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