The Functional Roles of ISG15/ISGylation in Cancer

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2023 Feb 11

PMID 36771004

Authors

Yin Yuan

Hai Qin

HuiLong Li

Wanjin Shi

Lichen Bao

Shengtao Xu

Jun Yin

Lufeng Zheng

Affiliations

Soon will be listed here.

Abstract

The protein ISG15 encoded by interferon-stimulated gene (ISG) 15 is the first identified member of the ubiquitin-like protein family and exists in the form of monomers and conjugated complexes. Like ubiquitin, ISG15 can mediate an ubiquitin-like modification by covalently modifying other proteins, known as ISGylation. There is growing evidence showing that both the free and conjugated ISG15 are involved in multiple key cellular processes, including autophagy, exosome secretion, DNA repair, immune regulation, and cancer occurrence and progression. In this review, we aim to further clarify the function of ISG15 and ISGylation in cancer, demonstrate the important relationship between ISG15/ISGylation and cancer, and emphasize new insights into the different roles of ISG15/ISGylation in cancer progression. This review may contribute to therapeutic intervention in cancer. However, due to the limitations of current research, the regulation of ISG15/ISGylation on cancer progression is not completely clear, thus further comprehensive and sufficient correlation studies are still needed.

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References

Lo P, Yao Y, Lee J, Zhang Y, Huang W, Kane M . LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer. Elife. 2018; 7. PMC: 5809145. DOI: 10.7554/eLife.31334. View

Xue X, Tian X, Zhang C, Miao Y, Wang Y, Peng Y . YAP ISGylation increases its stability and promotes its positive regulation on PPP by stimulating 6PGL transcription. Cell Death Discov. 2022; 8(1):59. PMC: 8837792. DOI: 10.1038/s41420-022-00842-8. View

Tecalco Cruz A, Mejia-Barreto K . Cell type-dependent regulation of free ISG15 levels and ISGylation. J Cell Commun Signal. 2017; 11(2):127-135. PMC: 5440350. DOI: 10.1007/s12079-017-0385-7. View

Feng Q, Sekula D, Guo Y, Liu X, Black C, Galimberti F . UBE1L causes lung cancer growth suppression by targeting cyclin D1. Mol Cancer Ther. 2008; 7(12):3780-8. PMC: 2638083. DOI: 10.1158/1535-7163.MCT-08-0753. View

Tecalco-Cruz A, Cortes-Gonzalez C, Cruz-Ramos E, Ramirez Jarquin J, Romero-Mandujano A, Sosa-Garrocho M . Interplay between interferon-stimulated gene 15/ISGylation and interferon gamma signaling in breast cancer cells. Cell Signal. 2018; 54:91-101. DOI: 10.1016/j.cellsig.2018.11.021. View

Mustachio L, Kawakami M, Lu Y, Rodriguez-Canales J, Mino B, Behrens C . The ISG15-specific protease USP18 regulates stability of PTEN. Oncotarget. 2016; 8(1):3-14. PMC: 5352120. DOI: 10.18632/oncotarget.13914. View

Sadler A, Williams B . Interferon-inducible antiviral effectors. Nat Rev Immunol. 2008; 8(7):559-68. PMC: 2522268. DOI: 10.1038/nri2314. View

DCunha J, Ramanujam S, WAGNER R, Witt P, KNIGHT Jr E, Borden E . In vitro and in vivo secretion of human ISG15, an IFN-induced immunomodulatory cytokine. J Immunol. 1996; 157(9):4100-8. View

Deng S, Marmorstein R . Protein N-Terminal Acetylation: Structural Basis, Mechanism, Versatility, and Regulation. Trends Biochem Sci. 2020; 46(1):15-27. PMC: 7749037. DOI: 10.1016/j.tibs.2020.08.005. View

10.

DCunha J, KNIGHT Jr E, Haas A, Truitt R, Borden E . Immunoregulatory properties of ISG15, an interferon-induced cytokine. Proc Natl Acad Sci U S A. 1996; 93(1):211-5. PMC: 40208. DOI: 10.1073/pnas.93.1.211. View

11.

Zhu L, Wu J, Liu H . Downregulation of HERC5 E3 ligase attenuates the ubiquitination of CtBP1 to inhibit apoptosis in colorectal cancer cells. Carcinogenesis. 2021; 42(8):1119-1130. DOI: 10.1093/carcin/bgab053. View

12.

Owhashi M, Taoka Y, Ishii K, Nakazawa S, Uemura H, Kambara H . Identification of a ubiquitin family protein as a novel neutrophil chemotactic factor. Biochem Biophys Res Commun. 2003; 309(3):533-9. DOI: 10.1016/j.bbrc.2003.08.038. View

13.

Hare N, Chan B, Chan E, Kaufman K, Britton W, Saunders B . Microparticles released from Mycobacterium tuberculosis-infected human macrophages contain increased levels of the type I interferon inducible proteins including ISG15. Proteomics. 2015; 15(17):3020-9. DOI: 10.1002/pmic.201400610. View

14.

Kariri Y, Alsaleem M, Joseph C, Alsaeed S, Aljohani A, Shiino S . The prognostic significance of interferon-stimulated gene 15 (ISG15) in invasive breast cancer. Breast Cancer Res Treat. 2020; 185(2):293-305. PMC: 7867506. DOI: 10.1007/s10549-020-05955-1. View

15.

Jeon Y, Yoo H, Chung C . ISG15 and immune diseases. Biochim Biophys Acta. 2010; 1802(5):485-96. PMC: 7127291. DOI: 10.1016/j.bbadis.2010.02.006. View

16.

Burks J, Reed R, Desai S . Free ISG15 triggers an antitumor immune response against breast cancer: a new perspective. Oncotarget. 2015; 6(9):7221-31. PMC: 4466680. DOI: 10.18632/oncotarget.3372. View

17.

Lertsooksawat W, Wongnoppavich A, Chairatvit K . Up-regulation of interferon-stimulated gene 15 and its conjugation machinery, UbE1L and UbcH8 expression by tumor necrosis factor-α through p38 MAPK and JNK signaling pathways in human lung carcinoma. Mol Cell Biochem. 2019; 462(1-2):51-59. DOI: 10.1007/s11010-019-03609-5. View

18.

Liu Y, Tavana O, Gu W . p53 modifications: exquisite decorations of the powerful guardian. J Mol Cell Biol. 2019; 11(7):564-577. PMC: 6736412. DOI: 10.1093/jmcb/mjz060. View

19.

Kim Y, Kim W, Jeong P, Ha Y, Kang H, Yun S . Novel combination markers for predicting survival in patients with muscle invasive bladder cancer: USP18 and DGCR2. J Korean Med Sci. 2014; 29(3):351-6. PMC: 3945129. DOI: 10.3346/jkms.2014.29.3.351. View

20.

Recht M, Borden E, KNIGHT Jr E . A human 15-kDa IFN-induced protein induces the secretion of IFN-gamma. J Immunol. 1991; 147(8):2617-23. View