ISG15: leading a double life as a secreted molecule

Bogunovic, Dusan; Boisson–Dupuis, Stéphanie; Casanova, Jean‐Laurent

doi:10.1038/emm.2013.36

Cited by 98 publications

(87 citation statements)

References 76 publications

(104 reference statements)

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“…On the other hand, an intracellular free-form of ISG15 and extracellular ISG15 are reported to have important biological functions. 26,27) We detected both forms of ISG15 in RAW-ISG cell extracts and the conditioned medium, respectively (Suppl . Figs.…”

Section: Isg15 Suppresses Atp6v0d2mentioning

confidence: 99%

ISG15 Regulates RANKL-Induced Osteoclastogenic Differentiation of RAW264 Cells

Takeuchi

Shimakawa

Tamura

et al. 2015

Biological & Pharmaceutical Bulletin

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Interferon-stimulated gene 15 kDa (ISG15) is a protein upregulated by interferon-β that negatively regulates osteoclastogenesis. We investigated the role of ISG15 in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenic differentiation of murine RAW264 cells. RANKL stimulation induced ISG15 expression in RAW264 cells at both the mRNA and protein levels. Overexpression of ISG15 in RAW264 cells resulted in suppression of cell fusion in RANKL-stimulated cells as well as the reduced expression of ATP6v0d2, a gene essential for cell fusion in osteoclastogenic differentiation. These results suggest that ISG15 suppresses RANKL-induced osteoclastogenesis, at least in part, through inhibition of ATP6v0d2 expression.Key words interferon-stimulated gene 15 kDa (ISG15); osteoclast; interferon; receptor activator of nuclear factor-κB ligand (RANKL); RAW264; ATP6v0d2Interferon-α/β is a multifunctional cytokine that exerts various biological functions in immunity, cell differentiation, and so on via the induction of downstream genes called interferonstimulated genes (ISGs).1,2) Interferon-stimulated gene 15 kDa (ISG15), a ubiquitin-like protein, is one of the proteins that are most upregulated by interferon stimulation.3,4) Upon stimulation of the cells with interferon or pathogenic materials such as lipopolysaccharides, the expression of ISG15 and several other enzymes that catalyze protein modification with ISG15 (ISGylation) is induced, followed by the ISGylation of various cellular proteins. ISGylation affects the nuclear factor-kappa B (NF-κB) signaling pathway as well as the activity of doublestranded RNA-activated protein kinase, 5,6) both of which have important roles in osteoclastogenic differentiation. 7,8) Osteoclasts are tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells derived from monocyte/macrophage lineage cells. 7,9) Receptor activator of nuclear factor-κB ligand (RANKL) is essential for the induction of osteoclastogenesis.10) The murine RAW264 cell line is a useful model of osteoclastogenesis as, upon stimulation with RANKL, RAW264 cells differentiate into TRAP-positive mononuclear cells, which subsequently undergo cell fusion to form TRAPpositive multinuclear osteoclasts. In vivo, osteoclastogenesis is tightly controlled by factors produced from cells such as osteoblasts and osteocytes, and deregulation of osteoclastogenesis results in various diseases such as osteoporosis. 7,9,11,12)

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Section: Isg15 Suppresses Atp6v0d2mentioning

confidence: 99%

ISG15 Regulates RANKL-Induced Osteoclastogenic Differentiation of RAW264 Cells

Takeuchi

Shimakawa

Tamura

et al. 2015

Biological & Pharmaceutical Bulletin

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“…Apart from its intracellular protein-conjugating functions, ISG15 can also be secreted from cells as free ISG15 where it can act as a cytokine or chemokine stimulating the production of type II IFN, enhancing natural killer cell activity and proliferation or functioning as a strong neutrophil chemoattractant (25,26). Thus, free ISG15 has strong immunomodulatory properties; however, the biologic role of free ISG15 has been understudied and the mechanisms promoting its liberation are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

ISG15 Is a Critical Microenvironmental Factor for Pancreatic Cancer Stem Cells

et al. 2014

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Cancer stem cells (CSC) are thought to play a major role in the development and metastatic progression of pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Likewise, the tumor microenvironment contributes critical support in this setting, including from tumor stromal cells and tumor-associated macrophages (TAM) that contribute structural and paracrine-mediated supports, respectively. Here, we show that TAMs secrete the IFN-stimulated factor ISG15, which enhances CSC phenotypes in PDAC in vitro and in vivo. ISG15 was preferentially and highly expressed by TAM present in primary PDAC tumors resected from patients. ISG15 was secreted by macrophages in response to secretion of IFNb by CSC, thereby reinforcing CSC selfrenewal, invasive capacity, and tumorigenic potential. Overall, our work demonstrates that ISG15 is a previously unrecognized support factor for CSC in the PDAC microenvironment with a key role in pathogenesis and progression. Cancer Res; 74(24); 7309-20. Ó2014 AACR.

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“…A series of distinct enzymes are involved in the process of protein ISGylation, including ubiquitin-activating enzyme E1 homolog (UBE1L) (14,15), a conjugating enzyme, ubiquitin carrier protein L6 (UBCH8) (E2) (16,17), protein ligases (E3) (18)(19)(20)(21), and an ISG15-specific protease USP18 (22,23), as well as some viral proteins (24). Interestingly, ISG15 and the majority of its modification enzymes are encoded by ISGs (25), indicating that protein ISGylation is a tightly regulated process and plays important roles in immune responses (26). Protein ISGylation is strongly enhanced upon pathogen infection and cellular stress related o IFN induction (25).…”

mentioning

confidence: 99%

Type I IFN induces protein ISGylation to enhance cytokine expression and augments colonic inflammation

Fan

Miyauchi-Ishida

Arimoto

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Type I IFNs have broad activity in tissue inflammation and malignant progression that depends on the expression of IFN-stimulated genes (ISGs). ISG15, one such ISG, can form covalent conjugates to many cellular proteins, a process termed "protein ISGylation." Although type I IFNs are involved in multiple inflammatory disorders, the role of protein ISGylation during inflammation has not been evaluated. Here we report that protein ISGylation exacerbates intestinal inflammation and colitis-associated colon cancer in mice. Mechanistically, we demonstrate that protein ISGylation negatively regulates the ubiquitin-proteasome system, leading to increased production of IFN-induced reactive oxygen species (ROS). The increased cellular ROS then enhances LPS-induced activation of p38 MAP kinase and the expression of inflammation-related cytokines in macrophages. Thus our studies reveal a regulatory role for protein ISGylation in colonic inflammation and its related malignant progression, indicating that targeting ubiquitin-activating enzyme E1 homolog has therapeutic potential in treating inflammatory diseases.

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ISG15: leading a double life as a secreted molecule

Cited by 98 publications

References 76 publications

ISG15 Regulates RANKL-Induced Osteoclastogenic Differentiation of RAW264 Cells

ISG15 Regulates RANKL-Induced Osteoclastogenic Differentiation of RAW264 Cells

ISG15 Is a Critical Microenvironmental Factor for Pancreatic Cancer Stem Cells

Type I IFN induces protein ISGylation to enhance cytokine expression and augments colonic inflammation

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