SLP-76 Adaptor Binding to SUMO-RANGAP1 of the Nuclear Pore Complex Regulates Multiple Aspects of T-cell Immunity

Abstract

Abstract While immune cell adaptors regulate various proximal events in T cell signaling, the direct regulation of the nuclear pore complex (NPC) has not been reported. On the cytoplasmic side of the NPC, there are cytoplasmic filaments composed of two fundamental proteins RanGAP1 and RanBP2. We previously showed that the immune cell adaptor SLP-76 binds directly to SUMO-RanGAP1 of cytoplasmic fibrils of the NPC, and that this interaction is needed for optimal NFATc1 and NF-κB p65 nuclear entry in T cells (Liu et al., 2015 Mol Cell 59, 840–9). The use of a mutant form of SLP-76 that is unable to bind to RanGAP1 (i.e. K56E) reduced nuclear entry and T-cell cytokine production by >60%. It represents the second step in NFATc1 entry into the nucleus of T-cells following classic NFATc de-phosphorylation by calcineurin. We now show that K56E mutant reduced toll-like receptor induction of NF-κB nuclear entry (innate signaling) and that T-cells from K56E mutant mice show major defects in T-cell proliferation and immunity. Our findings further underscore the importance of this direct regulation of NPC function in T cell function.