{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUSP12 is a ubiquitin‐specific protease that functions as a central component of multisubunit deubiquitinating enzyme complexes. It forms stable complexes with key cofactors such as UAF1 and WDR20, which together modulate its catalytic efficiency through allosteric mechanisms and dynamic subcellular targeting. Structural studies have revealed that UAF1 binds at the distal end of USP12’s Fingers domain and, along with WDR20 contacting a loop near the catalytic center, enhances enzymatic activity without altering substrate affinity. These observations indicate that USP12, similar to its paralogs, is precisely regulated by cofactor binding, which may also dictate substrate specificity and cellular localization."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn prostate cancer, USP12 exerts pro‐proliferative effects by directly deubiquitinating the androgen receptor (AR), thereby stabilizing it and enhancing its transcriptional activity. Furthermore, USP12, in complex with UAF1 and WDR20, deubiquitinates and stabilizes Akt phosphatases such as PHLPP1, ultimately reducing active Akt levels and modulating downstream survival signals."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUSP12 also modulates critical developmental and neurological pathways. It is a negative regulator of Notch signaling, where deubiquitination of the nonactivated receptor alters its lysosomal trafficking to impact surface levels and activity. In models of Huntington’s disease, USP12 has been shown to induce neuronal autophagy and alleviate mutant huntingtin toxicity—even through mechanisms independent of its catalytic activity—thereby contributing to neuroprotection."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn viral pathogenesis, USP12 is co-opted by oncogenic viruses. It is recruited into complexes by human papillomavirus E1 helicase to support viral DNA replication and, similarly, associates with Epstein–Barr virus nuclear proteins to modulate host gene expression critical for transformation. These interactions underscore its importance not only in cellular regulation but also in facilitating efficient viral propagation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these contexts, USP12 plays diverse roles in tumor biology. In lung and hepatocellular carcinomas, alterations in USP12 expression affect tumor cell proliferation. For instance, deubiquitination of RRM2 by USP12 in non‐small cell lung cancer cells alleviates DNA replication stress, while in other settings, its activity impacts oncogenic transcription factors such as c‐Myc. Moreover, USP12 expression levels have been linked to immune microenvironment modulation, with its downregulation fostering an immunosuppressive secretome that may desensitize tumors to immunotherapies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUSP12 is further implicated in immune regulation. In myeloid-derived suppressor cells, USP12 deubiquitinates and stabilizes the NF-κB subunit p65, thereby enhancing the suppressive functions of these cells and modulating CD8⁺ T-cell responses within the tumor microenvironment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, USP12 contributes to cellular adaptation under mechanical stress. In human periodontal ligament cells subjected to cyclic tension, USP12 is upregulated as an adaptive response, where its depletion triggers endoplasmic reticulum stress and enhances osteogenesis via activation of the PERK/eIF2α/ATF4 pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Martin A Cohn, Younghoon Kee, Wilhelm Haas, et al. 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