{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUSP27X functions as a multifaceted deubiquitinase that modulates key regulatory proteins involved in gene expression and tumorigenesis. In the nucleus, USP27X acts independently of classical complexes to regulate histone H2B monoubiquitination, thereby impacting transcriptional programs critical for cell proliferation and tumor growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In parallel, USP27X deubiquitinates phosphorylated Bim, stabilizing this pro‐apoptotic factor to counteract ERK-dependent degradation and promote apoptosis in tumor cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Furthermore, USP27X enhances the stability of Snail1 by removing degradative ubiquitin signals, a process that underpins epithelial-to-mesenchymal transition (EMT), cancer-associated fibroblast activation, metastasis, and chemoresistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in tumor cell biology, USP27X modulates innate immune signaling. It interacts directly with cyclic GMP-AMP synthase (cGAS) to cleave K48-linked ubiquitination chains, thereby stabilizing cGAS and promoting the production of the antiviral second messenger 2’3’-cGAMP."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Conversely, USP27X also targets RIG-I by removing K63-linked polyubiquitin, functioning as a negative regulator that fine tunes type I interferon responses during RNA virus infection."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, in the context of death receptor signaling, heightened USP27X activity reduces cellular FLIP levels via interaction with TRIM28, thereby sensitizing cells to extrinsic apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies reveal that USP27X contributes to oncogenic signaling by stabilizing proteins such as CBX2, where phosphorylation-dependent enhancement of its interaction with CBX2 promotes malignant progression in cancers like breast cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In the realm of neural development, functional disruption of USP27X through pathogenic variants has been implicated in X-linked intellectual disability (XLID105), highlighting its critical role in neurodevelopment and cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Boyko S Atanassov, Ryan D Mohan, Xianjiang Lan, et al. 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