{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUbiquitin C‐terminal hydrolase L3 (UCH‐L3) is a deubiquitinating enzyme with multifaceted roles in maintaining cellular homeostasis. In renal epithelial cells, UCH‐L3 promotes the recycling of the epithelial sodium channel (ENaC) by counteracting its ubiquitination, thereby sustaining apical channel density and normal transepithelial sodium transport."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In parallel, UCH‐L3 functions in the reproductive system where its localization to the oocyte cortex and association with the meiotic spindle are critical for fertilization and proper meiotic progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in epithelial integrity and reproduction, UCH‐L3 is instrumental in regulating key aspects of cellular metabolism and differentiation. It contributes to neuroprotection by processing aberrant ubiquitin species such as UBB(+1), whose accumulation is implicated in tauopathies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, UCH‐L3 enhances insulin signaling and adipogenesis, a function underscored by impaired adipocyte differentiation in its absence."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Its down‐regulation in the aging hippocampus suggests an involvement in the proteolytic clearance of oxidatively damaged proteins"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", while the stabilization of Smad1 by UCH‐L3 further promotes osteoblast differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Additionally, loss of UCH‐L3 activity leads to an up-regulation of AMP-activated protein kinase (AMPK) and enhanced fatty acid β-oxidation, indicating its contribution to whole-body energy metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUCH‐L3 is also key to maintaining protein quality control in muscle, where its deficiency results in the accumulation of polyubiquitinated proteins and activation of stress responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Beyond its role in proteostasis, aberrant expression of UCH‐L3 has been implicated in oncogenesis, acting as a novel driver in bladder cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", and in lung fibrosis, where UCH‐L3-mediated stabilization of p300 enhances chemokine transcription and drives profibrotic macrophage polarization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Together, these findings reveal UCH‐L3 as a versatile regulator of ubiquitin-dependent processes across diverse tissues, impacting ion channel dynamics, reproductive competence, neuronal integrity, metabolic homeostasis, and tissue remodeling.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael B Butterworth, Robert S Edinger, Huib Ovaa, et al. 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