{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nISG15 is a ubiquitin‐like modifier that is robustly induced by type I interferons and plays diverse, context‐dependent roles in innate immunity. Intracellularly, ISG15 is covalently attached to newly synthesized proteins (“ISGylation”), a process that in humans is crucial not for broad antiviral defense per se but for fine‐tuning interferon signaling. In ISG15‐deficient patients, failure to sustain USP18—a potent negative regulator of IFN‐α/β responses—leads to amplified type I IFN activity, predisposing to autoinflammation and enhanced susceptibility to mycobacterial disease. Furthermore, ISG15 is secreted by immune and nonimmune cells, and extracellular ISG15 acts as a cytokine by engaging the integrin LFA‐1 receptor to stimulate IFN‐γ production, thereby orchestrating additional immune responses."}, {"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": "\nISG15-mediated conjugation extends to an impressively broad range of viral and cellular targets, thereby directly affecting viral replication and host defense. Mass spectrometry–based proteomic studies have catalogued hundreds of targets, and structural analyses have delineated the two–domain “beta‐grasp” fold that underlies ISG15’s function as a protein modifier."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " By modifying key viral proteins—including the influenza A virus NS1 protein, HIV-1 Gag, Ebola virus VP40, and the human papillomavirus L1 capsid—ISGylation can disrupt critical interactions (such as nuclear import and interactions with ubiquitin ligases) that viruses exploit for replication and release."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": " The E3 ligase HERC5, which is associated with translating ribosomes, ensures that ISG15 is conjugated cotranslationally to a wide array of substrates, including the transcription factor IRF3 whose sustained activation bolsters antiviral gene expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In addition, insights from review articles and studies on deubiquitinating enzymes (DUBs) reveal that several DUBs can remove ISG15 from proteins, and that ISGylation may also activate cellular kinases such as PKR to inhibit translation in the absence of infection."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in antiviral defense, ISG15 modulates several fundamental cellular processes. Its ability to form mixed chains with ubiquitin alters protein turnover and homeostasis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ", while ISGylation of specific targets such as BECN1 governs autophagy and receptor degradation, as well as exosome release."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " In the context of cancer, aberrant ISG15 expression has been implicated in promoting cell migration and metastasis in breast cancer, whereas its conjugation to p53 may enhance tumor suppressor activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "29"}]}, {"type": "t", "text": " Moreover, ISG15 can exhibit proviral properties in certain contexts—for example, by facilitating hepatitis C virus production—while also restricting infection by intracellular bacteria such as Listeria"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "was also informative on protein turnover, and"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": "highlights bacterial restriction). Collectively, these observations underscore the multifaceted roles of ISG15 in regulating immune responses, protein quality control, autophagy, and tumor biology, while linking cellular stress and aging to inflammatory outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "27"}, {"type": "fg_f", "ref": "19"}, {"type": "fg_f", "ref": "28"}, {"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "David Meraro, Merav Gleit-Kielmanowicz, Hansjörg Hauser, et al. 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