Abstract
Abstract Protective immune responses elicited by primary activation of CD4+ T cells via dendritic cells is an essential requirement to evade herpesvirus infections. Optineurin (OPTN), a selective autophagy adaptor protein, is a crucial host restriction factor for herpes simplex virus (HSV) infection. We observed a significant reduction in the basal level of MHCII expression in OPTN–/– DCs accompanied by a concomitant decrease in CD4+ T cell counts in OPTN–/– mouse model. We hypothesize that abrogation of antigen presentation via MHCII in DCs weakens adaptive immune responses, leading to severe HSV1 infection. In this study, we elucidate the mechanism of OPTN-mediated down-regulation of MHCII via AKT/mTOR/STAT3 pathway. Mechanistically, OPTN induces activation of mTORC2 sequentially upregulating AKT2 which adversely affects the activation of mTORC1 and STAT3 protein. This could be attributed to the dynamic interplay between AKT1 and AKT2. Our findings provide novel insights into how the absence of OPTN downregulates AKT2 and triggers STAT3 activation. Furthermore, aberrant activation of STAT3 influences transcriptional activity of MARCH1(an E3 ubiquitin ligase) via IL10. MARCH1 mediates ubiquitination of MHCII resulting in the reduction of MHCII expression in OPTN–/– and AKT2–/– DCs. This study represents the first comprehensive delineation of the signaling pathway involved in the regulation of MHCII, shedding light on the intricate interplay between OPTN, AKT, mTOR, STAT3, and MARCH1.
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