{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nREGγ (also known as PA28γ or PSME3) is a unique proteasome activator that facilitates the ATP‐ and ubiquitin‐independent degradation of intact regulatory proteins. By directly binding to its substrates, REGγ accelerates the turnover of key effectors—including transcription factors and cell cycle regulators such as p53, MAFA, and GSK3β—to fine‐tune diverse cellular processes such as cell cycle progression, apoptosis, and gene expression. Its activity is further modulated by post‐translational modifications (e.g. acetylation), which influence REGγ heptamerization and substrate engagement, and its expression is often transiently upregulated in cell types undergoing differentiation or stress, indicating its importance in maintaining protein homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nREGγ also plays multifaceted roles in disease and inflammatory responses. In the liver and other metabolic tissues, it modulates lipid biosynthesis, energy homeostasis, and autophagy by controlling the stability of proteins such as the HCV core and SirT1—mechanisms that influence steatosis, tumor initiation, and protection from metabolic stress. In parallel, REGγ regulates immune responses by impacting antigen processing, the NF‐κB signaling cascade, and cytokine production; its dysregulation has been linked to aberrant inflammatory bowel phenotypes, altered defense against infections, and even changes in apoptotic thresholds in various cell types. Moreover, genetic deficiency or altered regulation of REGγ contributes to pathologies ranging from skin hyperproliferation and autoimmune disease to compromised gametogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its central roles in protein quality control and metabolic as well as immunological regulation, REGγ is implicated in the maintenance of tissue homeostasis in diverse organ systems. Its activity influences vascular endothelial cell migration and neovascularization, supports bone formation via modulation of the Wnt/β‐catenin pathway, and regulates neuronal protein turnover to prevent tau accumulation and promote cognitive function. REGγ’s function extends to reproductive tissues—where its expression correlates with fertility and proper gametogenesis—as well as to modulating inflammatory responses in the gut and testis. Together, these findings underscore REGγ as a key coordinator of proteostasis with broad impacts on cell survival, aging, and disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lance F Barton, Herbert A Runnels, Todd D Schell, et al. 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