A large Rab GTPase encoded by CRACR2A is a component of novel subsynaptic vesicles that transmit T cell activation signals

摘要

More than 60 members of the Rab GTPase family exist in the human genome. However, our current understanding is only limited to the role of small Rab GTPases in membrane trafficking. Here we show that CRACR2A encodes a lymphocyte-specific “large Rab GTPase” containing multiple functional domains including EF-hand motifs, proline-rich and Rab GTPase domains with an unconventional prenylation site. We demonstrate its direct role in activation of the Ca²⁺ and the Jnk signaling pathways upon T cell receptor (TCR) stimulation using gene silencing and transgenic animal models. Mechanistically, vesicles containing this Rab GTPase translocate from the Golgi into the immunological synapse (IS) to activate these signaling pathways. The interaction between proline-rich domain of this Rab GTPase and a guanidine nucleotide exchange factor/scaffold protein Vav1 is essential for accumulation of these vesicles at the IS. Furthermore, we demonstrate that GTP binding and prenylation are closely linked to membrane association, stability, and thereby activation of downstream signaling by this large GTPase. Our findings reveal a novel function of a large Rab GTPase in TCR signaling pathways, which is potentially shared by other GTPases with similar domain architecture.