Myo1g orchestrates MHC-II organization and trafficking in B lymphocytes

Major Histocompatibility Complex class II proteins are fundamental components of antigen presentation and immune response activation. Nonetheless, the mechanisms governing their distribution and vesicular trafficking remain partially understood. In this study, we establish that the unconventional myosin Myo1g, a type of motor protein, specifically interacts with MHC-II but not with MHC-I molecules and plays a crucial role in organizing B cell microvilli, and in antigen-processing pathways. Myo1g colocalizes with MHC-II within microvilli and vesicular compartments, facilitates MHC-II capping during activation, and supports the fusion of vesicles with lysosomes, which is essential for effective antigen degradation. The loss of Myo1g impairs the surface expression of MHC-II and LFA-1, alters the plasma membrane molecular distribution, and increases the surface expression of the invariant chain (CD74). Collectively, our findings identify Myo1g as an essential regulator of MHC-II trafficking and surface expression, thereby linking cytoskeletal dynamics to adaptive immune responses.