Sorting Nexin 27-dependent regulation of Lck and CD4 tunes the initial stages of T-cell activation.

ABSTRACT

Sorting nexin (SNX) 27 is a unique member of the SNX family of proteins that mediates the endosome-to-plasma membrane trafficking of cargos bearing a PSD95/Dlg1/ZO-1 (PDZ)-binding motif. In brain, SNX27 regulates synaptic plasticity, and its dysregulation contributes to cognitive impairment and neuronal degeneration. In T lymphocytes, SNX27 partners with diacylglycerol (DAG) kinase ζ (DGKζ) to facilitate polarized traffic and signaling at the immune synapse (IS). By silencing SNX27 expression in a human T cell line, we demonstrate that SNX27 is a key regulator of the early T cell tyrosine-based signaling cascade. SNX27 transcriptionally controls CD4 abundance in resting conditions, and that of its associated molecule, Lck. This guarantees the adequate recruitment of Lck at the IS that is indispensable for subsequent activation of tyrosine phosphorylation regulated events. In contrast, reduced SNX27 expression enhances NFκB-dependent induction of CXCR4 and triggers production of lytic enzymes and pro-inflammatory cytokines. These results provide mechanistic explanation to previously described SNX27 function in the control of immune synapse organization and indicate that impaired SNX27 expression contributes to CD4 T cell dysfunction.