{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUbiquitin‐specific protease 15 (USP15) plays critical roles in regulating major signaling pathways that control cellular growth and differentiation. Several studies demonstrate that USP15 modulates transforming growth factor–β (TGF‐β) family responses by deubiquitinating key components such as the type I TGF‐β receptor, receptor‐activated SMADs, and the inhibitory SMURF2 E3 ligase. In association with the COP9 signalosome, USP15 also stabilizes components of the β‐catenin destruction complex and promotes bone morphogenetic protein (BMP)–induced SMAD phosphorylation, thereby impacting oncogenic signaling and embryonic development."}, {"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": "\nUSP15 has also been implicated in the regulation of mitochondrial quality control and neuronal homeostasis. In models of Parkinson’s disease, USP15 counteracts Parkin‐mediated mitophagy by opposing the ubiquitination of mitochondrial substrates, and its knockdown can restore mitophagy defects due to reduced Parkin levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of immune regulation and antiviral responses, USP15 functions as a key negative regulator. It stabilizes proteins such as MDM2 to repress T cell activation and, in parallel, deubiquitinates components of innate immune signaling cascades. By removing degradative ubiquitin chains from proteins such as p53 and the E3 ligase TRIM25—as well as modulating RIG-I signaling via both deubiquitylating‐dependent and –independent mechanisms—USP15 fine‐tunes cytokine production and interferon responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUSP15 contributes significantly to the maintenance of genome integrity through its roles in DNA repair and cell cycle regulation. It promotes homologous recombination by deubiquitinating the BARD1 BRCT domain, which is instrumental for BRCA1–BARD1 complex retention at double‐strand breaks. In addition, USP15 facilitates the accumulation of topoisomerase IIα during G2 and early mitosis; its deficiency leads to defective decatenation of sister chromatids, resulting in aneuploidy. Moreover, USP15 stabilizes poly(ADP‐ribose) polymerase 1 (PARP1) thereby promoting efficient DNA repair in cancer cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nViral pathogenesis is yet another context in which USP15 exerts influence. It interacts with and stabilizes viral oncoproteins as well as regulatory factors. In human papillomavirus (HPV) infection, USP15 deubiquitinates and thereby stabilizes the E6 oncoprotein. Similarly, USP15 enhances the stability and function of the hepatitis B virus X protein, while its actions on HIV-1 Nef and other viral components can modulate viral protein turnover, highlighting USP15 as an attractive target in antiviral therapeutic strategies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther insights into USP15’s molecular versatility arise from studies of its roles in RNA processing and substrate specificity. Structural and biochemical analyses reveal that USP15 harbors unique DUSP and ubiquitin-like (UBL) domains that regulate its enzymatic activity and interactions with proteins involved in pre-mRNA splicing. Its binding to spliceosomal factors not only modulates histone deubiquitination events (such as the removal of ubiquitin from H2B) but also couples deubiquitination to efficient translational recovery of key regulatory proteins."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these molecular roles, USP15 is emerging as a pivotal regulator of tumorigenesis and tissue homeostasis in diverse disease contexts. Elevated expression of USP15 has been linked to progression in non–small cell lung cancer, hepatocellular carcinoma, and breast cancer where it prevents degradation of estrogen receptor–α. In addition, aberrant USP15 activity has been implicated in immunologic disorders such as psoriasis, in fibrotic conditions including hypertrophic scarring, and in metabolic regulation via antagonism of Nedd4‐mediated ubiquitination of IRS-2. In hematopoietic stem/progenitor cells, its functional interactions with factors such as TIFAB underpin its essential role in sustaining genome integrity and cell survival in acute myeloid leukemia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xiaohua Huang, Corinna Langelotz, Bettina K J Hetfeld-Pechoc, et al. 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