| First Author | Chu L | Year | 2024 |
| Journal | Cell Rep | Volume | 43 |
| Issue | 3 | Pages | 113870 |
| PubMed ID | 38421872 | Mgi Jnum | J:346158 |
| Mgi Id | MGI:7613912 | Doi | 10.1016/j.celrep.2024.113870 |
| Citation | Chu L, et al. (2024) HERC5-catalyzed ISGylation potentiates cGAS-mediated innate immunity. Cell Rep 43(3):113870 |
| abstractText | The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) is essential to elicit type I interferon cascade response; thus, the activity of cGAS must be strictly regulated to boost the antiviral innate immunity. Here, we report that cGAS is responsible for the DNA-induced ISG15 conjugation system. The E3 HERC5 catalyzes the ISGylation of cytoplasmic cGAS at lysine 21, 187, 219, and 458, whereas Ubl carboxy-terminal hydrolase 18 removes the ISGylation of cGAS. The interaction of cGAS and HERC5 depends on the cGAS C-terminal domain and the RRC1-4 and RRC1-5 domains of HERC5. Mechanically, HERC5-catalyzed ISGylation promotes DNA-induced cGAS oligomerization and enhances cGAS enzymatic activity. Deficiency of ISGylation attenuates the downstream inflammatory gene expression induced by the cGAS-STING axis and the antiviral ability in mouse and human cells. Mice deficient in Isg15 or Herc6 are more vulnerable to herpes simplex virus 1 infection. Collectively, our study shows a positive feedback regulation of the cGAS-mediated innate immune pathway by ISGylation. |
