Inhibition of Ubc13-mediated ubiquitination by GPS2 regulates multiple stages of B cell development

Abstract Non-proteolytic ubiquitin signaling mediated by K63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that G-Protein Suppressor 2 (GPS2) is a multi-functional protein regulating TNFα signaling and lipid metabolism in the adipose tissue through modulation of K63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2 resulting in developmental defects at multiple stages of B cell differentiation. Together, these finding reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells.