Editors' ChoiceImmunology

Adapting to the nucleus

Sci. Signal.  22 Sep 2015:
Vol. 8, Issue 395, pp. ec269
DOI: 10.1126/scisignal.aad4850

Antigen binding to the T cell receptor (TCR) stimulates the accumulation of signaling components, including kinases and adaptor proteins, at the intracellular face of the plasma membrane to activate T cells. The adaptor protein SLP-76 [Src homology 2 (SH2) domain–containing leukocyte protein of 76 kD] is required for phospholipase Cγ1 activation and Ca2+ mobilization; thus, SLP-76–deficient T cells show impaired activation. Liu et al. found that SLP-76 provides a second contribution to T cell activation at the nucleus. Confocal microscopy showed that TCR stimulation of mouse T cells resulted in the colocalization of SLP-76 and a SUMOylated form of the guanine nucleotide triphosphatase (GTPase)–activating protein RanGAP1 in cytoplasmic filaments of the nuclear pore complex. Both RanGAP1 and the GTPase Ran are required for the import of proteins from the cytosol into the nucleus. Coimmunoprecipitation experiments showed that maximal binding of SLP-76 to RanGAP1 occurred 10 to 20 minutes after TCR stimulation. Mutagenesis studies showed that mutation of Lys56 to alanine (K56E) in the N-terminal region of SLP-76 blocked its interaction with RanGAP1 but had no effect on TCR signaling events at the plasma membrane. The transcription factors NFATc1 and NF-κB are required for the expression of genes whose products are important for T cell activation. Whereas TCR stimulation of SLP-76–deficient J14 T cells in which wild-type SLP-76 was overexpressed resulted in efficient nuclear translocation of fluorescently tagged forms of NFATc1 and NF-κB, TCR stimulation of J14 cells expressing SLP-76 K56E exhibited impaired nuclear import of both transcription factors. Last, when T cells overexpressing either wild-type or K56E SLP-76 were injected into mice, exposed to antigen, recovered from the mice, and then restimulated with antigen in vitro, the cells expressing K56E SLP-76 showed a defective proliferative response. Together, these data suggest that in addition to mediating TCR-proximal signaling at the plasma membrane, SLP-76 further contributes to T cell activation by facilitating the import of critical transcription factors into the nucleus.

H. Liu, H. Schneider, A. Recino, C. Richardson, M. W. Goldberg, C. E. Rudd, The immune adaptor SLP-76 binds to SUMO-RANGAP1 at nuclear pore complex filaments to regulate nuclear import of transcription factors in T cells. Mol. Cell 59, 840–849 (2015). [PubMed]