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.