Autophagy-related protein VPS34 controls the homeostasis and function of macrophages

Abstract

Abstract Vacuolar protein sorting 34 (VPS34; also known as PIK3C3) plays a role in both canonical and noncanonical autophagy, key processes that control immune cell responsiveness to a variety of stimuli. Our previous studies found that VPS34 is a critical regulator that controls the development, homeostasis, and function of dendritic cells and T cells. In this study, we investigated the role of VPS34 in macrophage biology using myeloid cell-specific Vps34-deficient mice. We found that Vps34-deficient macrophages express increased surface levels of MHC class I and class II molecules. Interestingly, Vps34 ablation in macrophages caused a partial impairment in the homeostatic maintenance of TIM-4+ macrophages and defective uptake of apoptotic cells. In addition, myeloid cell-specific Vps34-deficient animals showed significantly reduced severity of experimental autoimmune encephalomyelitis (EAE), a primarily CD4+ T cell-mediated mouse model of multiple sclerosis. Importantly, peritoneal macrophages from mice deficient in the VPS34-associated protein RUBICON, which is critical for a noncanonical form of autophagy called light chain (LC) 3-associated phagocytosis (LAP), showed normal MHC class I, MHC class II, and TIM-4 expression and Rubicon−/− mice developed signs of EAE similar to wild-type control mice. These results suggested that the canonical autophagy-dependent activities of VPS34 play a critical role in controlling macrophage homeostasis and function. Collectively, our studies establish VPS34 as an important regulator of macrophage functions and macrophage-mediated regulation of EAE. Our findings also have important implications for the development of small-molecule inhibitors of VPS34 for therapeutic purposes.