MITA oligomerization upon viral infection is dependent on its N-glycosylation mediated by DDOST

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. Author summary Interferons (IFNs) play critical roles in controlling viral infection. Insufficient production of IFNs leads to chronic infection and disease progression. Here, we report that DDOST is an important regulator of the MITA/STING-mediated production of antiviral type I IFNs. DDOST knockdown impairs the MITA-mediated IFN response to HSV-1 and double-stranded DNA (dsDNA). Mechanistically, DDOST mediates HSV-1-induced N-glycosylation of MITA at certain residues, which is essential to promote MITA oligomerization and consequent immune functions. Moreover, the expression of endogenous DDOST was specifically low in the brain. Increasing the expression of Ddost in the mouse brain strengthens the local immune functions and prolongs the survival time of mice with HSE. These findings reveal a regulatory mechanism of MITA oligomerization and provide one explanation for the pathogenesis of HSE, which provides a clue for developing a new antiviral drug.