CRACR2A encodes a novel Ca2-binding Rab GTPase important for T cell receptor signalling (IRM10P.748)

Abstract

Abstract Ca2+ signalling is important for T cell stimulation and its impairment leads to immune deficiency. In T cells, Ca2+ entry is mediated by CRAC (Ca2+-release activated Ca2+) channels that consist of the pore component, Orai1 and the endoplasmic reticulum Ca2+ sensor, STIM1. We recently identified CRACR2A (CRAC channel regulator 2A) as an interacting partner of Orai1 and STIM1. Here we investigate the role of a novel isoform of CRACR2A that is predominantly expressed in immune cells. CRACR2A contains multiple functional domains including Ca2+-binding motifs and a C-terminal Rab GTPase domain. Different from small Rab GTPases, CRACR2A utilized a two-step activation mechanism of GTP binding and T cell receptor (TCR) stimulation to mediate its translocation into the immunological synapse. Defect in GTP binding or hydrolysis activity results in loss and gain of function respectively. CRACR2A played a predominant role in Ca2+ and mitogen-activated protein kinase (MAPK) signalling pathways. Furthermore, CRACR2A-deficient T cells showed impairment in Th1 differentiation. In support of these data, mice with T cell-specific deletion of CRACR2A showed a strong resistance to experimental autoimmune encephalomyelitis. Previously, small GTPase has been shown to play an important role in TCR signaling. Our study identifies the unexpected usage of a large Rab GTPase as a molecular switch to regulate TCR signalling pathways.