Antiviral adaptor MAVS positively regulates mitochondrial integrity and metabolic fitness in antigen receptor-activated B cells

The autoimmune disease systemic lupus erythematosus (SLE) is associated with increased systemic expression of type I interferons, in some cases due to dysregulation in nucleic acid-sensing innate pathways, such as the retinoic acid inducible gene-I (RIG-I) - mitochondrial antiviral signaling protein (MAVS) - type I IFN pathway. We have recently reported that MAVS is required for the autoimmune phenotype of FcgRIIB knockout mice in a B cell-dependent manner. Here we demonstrate that while MAVS deficient B cells were competent in BCR-initiated signaling cascade including calcium influx and phosphorylation of ERK, AKT and S6, they are defective in BCR-triggered proliferation beyond three divisions. Mitochondria of BCR-activated MAVS-deficient B cells exhibited damaged phenotype with features of swollen, diminished cristae, polarized TOM20 distribution and increased mitophagy, which was associated with reduced oxidative phosphorylation and slow cell death. RNA-seq analyses revealed dysregulated gene programs related to interferon signaling, cell cycle, lipid metabolism and biosynthesis in MAVS-deficient B cells. Interestingly, BCR cross-linking or calcium mobilization induced a rapid polymerization of MAVS, differing from viral RNA-initiated MAVS aggregation which takes hours to process. Thus, our results revealed a previously unrecognized BCR-MAVS-mitochondria signaling axis that promotes mitochondrial homeostasis critical for B cell proliferation and survival.