FIP200 governs plasma B cell differentiation by regulating mitochondrial homeostasis and heme biosynthesis 9012

Abstract Description Disruptions in metabolic homeostasis may substantially influence the immune response, and the development and activation of B lymphocytes is known to be particularly dependent on autophagy. We found that B cells deficient in FIP200, a mammalian autophagy sensor which complexes with ULK1/ATG13/ATG101 to initiate autophagy in response to a range of stimuli, failed to undergo normal immune cell reorganization in response to fasting. Furthermore, humoral immune responses were diminished due to decreased differentiation into antibody-secreting cells and reduced memory B cells. FIP200-deficient B cells exhibit defective mitophagy, leading to mitochondrial dysfunction and increased mROS, resulting in the formation of NLRP3 inflammasomes driving significant cell death. Moreover, single-cell RNAseq suggested that heme biosynthesis was affected in FIP200-deficient B cells; notably, the administration of heme was sufficient to rescue plasma cell differentiation of FIP200-deficient B cells. Thus, FIP200 determines B cell fates by controlling mitophagy and metabolic reprogramming. Funding Sources A portion of this research was funded by NIH grant R01AI135052 (to F.D.B.) and by The Ragon Institute of Mass General, MIT, and Harvard (to F.D.B.). Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)