ABSTRACT
The mediator of IRF3 activation (MITA, also named STING) is critical for immune responses to abnormal cytosolic DNA and has been considered an important drug target in the clinical therapy of tumors and autoimmune diseases. In the present study, we report that MITA undergoes DDOST-mediated N-glycosylation in the endoplasmic reticulum (ER) upon DNA viral infection. Selective mutation of DDOST-dependent N-glycosylated residues abolished MITA oligomerization and thereby its immune functions. Moreover, increasing the expression of Ddost in the mouse brain effectively strengthens the local immune response to herpes simplex virus-1 (HSV-1) and prolongs the survival time of mice with HSV encephalitis (HSE). Our findings reveal the dependence of N-glycosylation on MITA activation and provide a new perspective on the pathogenesis of HSE.
Subject(s)
Autoimmune Diseases , Encephalitis, Herpes Simplex , Herpesvirus 1, Human , Virus Diseases , Animals , Mice , GlycosylationABSTRACT
As a key dsDNA recognition receptor, cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) plays a vital role in innate immune responses. Activated cGAS, by sensing DNA, catalyzes the synthesis of the secondary messenger cyclic GMP-AMP (cGAMP), which subsequently activates downstream signaling to induce production of interferons and inflammatory cytokines. Here, we report Zyg-11 family member B (ZYG11B) as a potent amplifier in cGAS-mediated immune responses. Knockdown of ZYG11B impairs production of cGAMP and subsequent transcription of interferon and inflammatory cytokines. Mechanistically, ZYG11B enhances cGAS-DNA binding affinity, potentiates cGAS-DNA condensation, and stabilizes the cGAS-DNA condensed complex. Moreover, herpes simplex virus 1 (HSV-1) infection induces ZYG11B degradation in a cGAS-unrelated manner. Our findings not only reveal an important role of ZYG11B in the early stage of DNA-induced cGAS activation but also indicate a viral strategy to dampen the innate immune response.