HERC5-catalyzed ISGylation potentiates cGAS-mediated innate immunity

0301 basic medicine 03 medical and health sciences QH301-705.5 CP: Immunology Biology (General)
DOI: 10.1016/j.celrep.2024.113870 Publication Date: 2024-02-28T22:53:26Z
ABSTRACT
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 boost antiviral innate immunity. Here, we report that responsible for DNA-induced ISG15 conjugation system. E3 HERC5 catalyzes ISGylation cytoplasmic at lysine 21, 187, 219, and 458, whereas Ubl carboxy-terminal hydrolase 18 removes cGAS. interaction depends on C-terminal domain RRC1-4 RRC1-5 domains HERC5. Mechanically, HERC5-catalyzed promotes oligomerization enhances enzymatic activity. Deficiency attenuates downstream inflammatory gene expression induced by cGAS-STING axis ability in mouse human cells. Mice deficient Isg15 or Herc6 are more vulnerable herpes simplex virus 1 infection. Collectively, our study shows a positive feedback regulation cGAS-mediated immune pathway ISGylation.
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