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Review
. 2023 Jan 31;28(3):1337.
doi: 10.3390/molecules28031337.

The Functional Roles of ISG15/ISGylation in Cancer

Yin Yuan  1 , Hai Qin  2 , Huilong Li  1 , Wanjin Shi  1 , Lichen Bao  3 , Shengtao Xu  1 , Jun Yin  1 , Lufeng Zheng  1
Affiliations
Review

The Functional Roles of ISG15/ISGylation in Cancer

Yin Yuan et al. Molecules. .

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.

Keywords: ISG15; ISGylation; cancer; post-translational modification; ubiquitin-like protein.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The structure and function of ISG15. (A) the 3D representation of the ISG15 protein. (B) the secondary structure of the ISG15 protein. (C) physiological and pathological functions of ISG15. Include the role of ISG15 in antiviral and immune regulation, the harm of ISG15 defects, and the role of ISG15 in tumor proliferation and tumor immunity.
Figure 2
Figure 2
ISG15 in various cancers. (A) expression levels of ISG15 in different cancers. Data from TNMplot, significant differences by Mann-Whitney U test are marked with red [32]. * p < 0.05 vs. normal group. (B) the functional roles of free ISG15 in various cancers.
Figure 2
Figure 2
ISG15 in various cancers. (A) expression levels of ISG15 in different cancers. Data from TNMplot, significant differences by Mann-Whitney U test are marked with red [32]. * p < 0.05 vs. normal group. (B) the functional roles of free ISG15 in various cancers.
Figure 3
Figure 3
The role of ISGylation in cells. (A) inhibition of transcription by increased ISGylation levels of some proteins; (B) antagonism of ISGylation to the ubiquitin proteasome pathway; (C) ISG15 promotes p62-mediated autophagy.
Figure 4
Figure 4
The cascade reactions of ISGylation. Under the action of activating enzyme E1, the C-terminal of ISG15 and the active site cysteine (Cys) of E1 form a high-energy thioester bond, and this step requires ATP to provide energy; the activated ISG15 is then transferred to the conjugated enzyme; the cysteine of E2 is also covalently linked in the form of a thioester bond; and finally, under the action of ligase E3, ISG15 is modified on the substrate protein. The deconjugating enzyme ISG15 can enzymatically hydrolyze ISG15 from the modified substrate, thus forming ISG15 recycling.
Figure 5
Figure 5
The dual-function of ISGylation in tumor cells. (A) the cancer-promoting effects of ISGylation; (B) the tumor-suppressive effects of ISGylation.
Figure 6
Figure 6
The function of ISG15 modification system in tumor. UBA7 can inhibit the growth of human lung cancer cells; UBCH8 can promote the invasion of breast cancer cells; HERC5 has both tumor-promoting and tumor-suppressing functions; USP18 has a positive role in promoting cancer.
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