3β-hydroxysteroid-Δ24 reductase dampens anti-viral innate immune responses by targeting K27 ubiquitination of MAVS and STING

Abstract

ABSTRACT The mechanism by which lipid metabolism regulates innate immunity is unknown. Here, we report that the key enzyme in cholesterol synthesis, 3β-hydroxysteroid-Δ24 reductase (DHCR24), is inhibited by viral infection. DHCR24 deficiency significantly promotes interferon production and interferon-stimulated gene expression. Inhibition of DHCR24 enzyme activity or the addition of the precursor 24-dehydrocholesterol (24-DHC) can augment innate immunity. Mechanistically, DHCR24 interacts with MAVS or STING, and DHCR24 impairs K27-linked ubiquitination of MAVS mediated by TRIM21 and K27-linked ubiquitination of STING mediated by AMFR, blocking the activation of MAVS and STING, respectively. Collectively, DHCR24 plays a negative role in regulating innate immune responses that may be targeted to improve immunity. IMPORTANCE The precise regulation of the innate immune response is essential for the maintenance of homeostasis. MAVS and STING play key roles in immune signaling pathways activated by RNA and DNA viruses, respectively. Here, we showed that DHCR24 impaired the antiviral response by targeting MAVS and STING. Notably, DHCR24 interacts with MAVS and STING and inhibits TRIM21-triggered K27-linked ubiquitination of MAVS and AMFR-triggered K27-linked ubiquitination of STING, restraining the activation of MAVS and STING, respectively. Together, this study elucidates how one cholesterol key enzyme orchestrates two antiviral signal transduction pathways.