Purine Synthesis Pathways Activate mTORC1 in B cells

The mechanistic target of rapamycin complex 1 (mTORC1) regulates cellular metabolism by sensing growth factors and nutrient availability to support growth and division. In quiescent B cells, mTORC1 activity is low, but it rapidly increases upon engagement of activating receptors, such as antigen receptors, co-receptors, and Toll-like receptors. The magnitude of mTORC1 activity fine-tunes both the proliferative capacity and protein synthesis potential of activated B cells, broadly influencing humoral immunity. Elevated mTORC1 activity has been reported in lymphocytes from patients with autoimmune diseases, and pharmacological inhibition of mTORC1 reduces antibody titers. We and others have previously shown that the E3 ubiquitin ligase Itch negatively modulates mTORC1 activity in B cells and regulates antibody levels in humans and mice. Here, we investigate how Itch regulates mTORC1 activity following TLR9 engagement in B cells. Our results show an unexpected role for Itch in limiting purine synthesis-dependent mTORC1 activation in B cells. Purine sensing represents a novel target for fine control of mTORC1 activity in B cells, with therapeutic potential for diseases where mTORC1 hyperactivation contributes to pathogenesis.