ISG15 and ISGylation in Human Diseases

Abstract

Type I Interferons (IFNs) induce the expression of >500 genes, which are collectively called ISGs (IFN-stimulated genes). One of the earliest ISGs induced by IFNs is ISG15 (Interferon-Stimulated Gene 15). Free ISG15 protein synthesized from the ISG15 gene is post‑translationally conjugated to cellular proteins and is also secreted by cells into the extracellular milieu. ISG15 comprises two ubiquitin-like domains (UBL1 and UBL2), each of which bears a striking similarity to ubiquitin, accounting for its earlier name ubiquitin cross-reactive protein (UCRP). Like ubiquitin, ISG15 harbors a characteristic β‑grasp fold in both UBL domains. UBL2 domain has a conserved C‑terminal Gly-Gly motif through which cellular proteins are appended via an enzymatic cascade similar to ubiquitylation called ISGylation. ISG15 protein is minimally expressed under physiological conditions. However, its IFN‑dependent expression is aberrantly elevated or compromised in various human diseases, including multiple types of cancer, neurodegenerative disorders (Ataxia Telangiectasia and Amyotrophic Lateral Sclerosis), inflammatory diseases (Mendelian Susceptibility to Mycobacterial Disease (MSMD), bacteriopathy and viropathy), and in the lumbar spinal cords of veterans exposed to Traumatic Brain Injury (TBI). ISG15 and ISGylation have both inhibitory and/or stimulatory roles in the etiology and pathogenesis of human diseases. Thus, ISG15 is considered a “double-edged sword” for human diseases in which its expression is elevated. Because of the roles of ISG15 and ISGylation in cancer cell proliferation, migration, and metastasis, conferring anti-cancer drug sensitivity to tumor cells, and its elevated expression in cancer, neurodegenerative disorders, and veterans exposed to TBI, both ISG15 and ISGylation are now considered diagnostic/prognostic biomarkers and therapeutic targets for these ailments. In the current review, we shall cover the exciting journey of ISG15, spanning three decades from the bench to the bedside.

ISGylation of EMD promotes its interaction with PDHA to inhibit aerobic oxidation in lung adenocarcinoma

“…ISGylation is rarely induced under physiological conditions whereas abnormally elevated in various human diseases including several types of cancer. 43 ISGylation can be induced in many patterns in cancer. Firstly, ISGylation can be induced by type I interferon (IFN) produced in the tumour microenvironment.…”

“…ISGylation is rarely induced under physiological conditions whereas abnormally elevated in various human diseases including several types of cancer 43 . ISGylation can be induced in many patterns in cancer.…”

Coronaviral PLpro proteases and the immunomodulatory roles of conjugated versus free Interferon Stimulated Gene product-15 (ISG15)

“…Elevated levels of ISG15 are correlated with a number of human ailments such as cancer, neurodegeneration, inflammation, and assaults from pathogens [74] , [75] . Indeed, IFN has been used to treat certain types of cancer and specific viruses [76] .…”

Friend or foe: RIG- I like receptors and diseases

“…For instance, the UBL protein HLA-F adjacent transcription 10 (FAT10) suppresses the RIG-I-TRIM25 complex through binding and stabilizing the RIG-I protein, thereby dampening the RIG-I-mediated antiviral responses[ 111 ]. The other UBL protein, IFN-induced 15-kDa protein (ISG15), performs ISGylation (a ubiquitin-like modification) and activates MDA5 but reduces RIG-I intracellular levels [ [112] , [113] , [114] ]. Intriguingly, it has been recently found that SARS-CoV-2 utilizes autogenous papain-like protease to antagonize MDA5 ISGylation and evade host innate immunity, which may account for the SARS-CoV-2 immune evasion and the suppression of host IFN-I production[ 115 ].…”