Gigaxonin Potentiates Antiviral Innate Immune Responses by Targeting cGAS and TREX1

Innate immunity is the first line of defense against viral infections. Cyclic GMP-AMP synthase (cGAS) senses abnormal cytosolic double-stranded DNA (dsDNA) and triggers the production of interferon and proinflammatory cytokines to eliminate viruses, whereas three-prime repair exonuclease 1 (TREX1) directly digests cytosolic dsDNA, thereby preventing aberrant activation of cGAS. The precise regulation of the antiviral response by cGAS and TREX1 remains incompletely understood. In this study, it is reported that gigaxonin potentiates antiviral innate immune responses by targeting both TREX1 and cGAS. Gigaxonin controls TREX1 turnover in the steady state by mediating its ubiquitination and proteasomal degradation. It also enhances the ubiquitination of cGAS and increases its enzymatic activity in response to infection with herpes simplex virus type 1 (HSV-1). Furthermore, it is found that the binding of cGAS to gigaxonin is induced by HSV-1 infection and that this interaction inhibits the TREX1-gigaxonin interaction. The findings highlight the dynamic role of gigaxonin in enhancing antiviral innate immune responses by targeting both TREX1 and cGAS, suggesting that targeting gigaxonin may constitute a novel therapeutic approach for combating infectious diseases.