Deciphering the signaling pathway involved in the regulation of MHC II 3453

Abstract Description Adaptive immune responses depend on the Major Histocompatibility Complex II (MHC II) for the presentation of immunogenic peptides to CD4+ T cells. Antigen Presentation via MHC II requires efficient regulation of its surface expression. MARCH1, a key E3 ligase, plays a central role in the ubiquitination of MHC II, thereby modulating its steady-state surface levels. Despite its importance, the signaling cascade governing the regulation of the MARCH1/MHC II axis remains poorly understood. In this study, we elucidate the functional consequences using HSV-1, a prototypical DNA virus, as a model system. We identify a widely expressed cytoplasmic protein, optineurin as a master regulator of the AKT/mTOR/STAT3 signaling axis, which in turn modulates MARCH1 levels and governs MHC II regulation. To dissect this pathway, we employ transgenic models including Rictor –/–, Akt1–/–, Akt2–/–, Rptor –/–, and Optn–/– to explore the dynamic interplay between these critical signaling components. Our findings reveal that the canonical STAT3 activation via the AKT/mTOR pathway is perturbed in the absence of optineurin, leading to decreased surface expression of MHC II on dendritic cells. This results in impaired antigen presentation, which exacerbates HSV-1 infection. Overall, this study represents the first comprehensive characterization of the signaling network regulating MHC II expression, providing new insights into the molecular mechanisms controlling immune function and pathogen defense. Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)