RAB4A DRIVES PROINFLAMMATORY CD4 T CELL SIGNALING VIA CD38-DEPENDENT NAD METABOLISM.

Rab4A, a small GTPase overexpressed in T cells of patients with systemic lupus erythematosus (SLE), has been shown to activate mechanistic target of rapamycin (mTOR) signaling, which promotes proinflammatory T cell development and predisposes to nephritis in SLE. In this study, we demonstrate that Rab4A facilitates the endocytic recycling and surface expression of CD38, which, in turn, triggers NAD depletion, activates mTOR complex 1, and suppresses interleukin-2 (IL-2) production in CD4 T cells. Rab4A-driven CD38-mediated NAD depletion elicits the accumulation of nicotinamide and ADP-ribose and secondary depletion of cyclic ADP-ribose. Surprisingly, rapamycin further enhanced CD38 expression and reduced IL-2 secretion, suggesting that IL-2 depletion is mTOR-independent. Alternatively, Rab4A-driven upregulation of CD38 promoted STAT3 expression and its acetylation, as well as FOXO1 expression, which underlies IL-2 depletion in CD4 T cells. These findings reveal a novel Rab4A-driven CD38 signaling axis that links receptor trafficking to proinflammatory metabolic pathways, providing new targets for treatment in SLE.