Abstract
Sorting nexin 27 (SNX27) recycles PSD-95, Dlg1, ZO-1 (PDZ) domain-interacting membrane proteins and is essential to sustain adequate brain functions. Here we define a fundamental SNX27 function in T lymphocytes controlling antigen-induced transcriptional activation and metabolic reprogramming. SNX27 limits the activation of diacylglycerol (DAG)-based signals through its high affinity PDZ-interacting cargo DAG kinase ζ (DGKζ). SNX27 silencing in human T cells enhanced T cell receptor (TCR)-stimulated activator protein 1 (AP-1)- and nuclear factor κB (NF-κB)-mediated transcription. Transcription did not increase upon DGKζ silencing, suggesting that DGKζ function is dependent on SNX27. The enhanced transcriptional activation in SNX27-silenced cells contrasted with defective activation of the mammalian target of rapamycin (mTOR) pathway. The analysis of Snx27−/− mice supported a role for SNX27 in the control of T cell growth. This study broadens our understanding of SNX27 as an integrator of lipid-based signals with the control of transcription and metabolic pathways.
Highlights
The sorting nexins (SNX) are proteins that regulate intracellular protein trafficking and endosomal signaling
We investigated the effect of Sorting nexin 27 (SNX27) in the magnitude of Ras activation following T cell receptor (TCR) triggering
Activation of the Ras pathway can be monitored by measuring surface abundance of CD69, a C-type lectin that is transcriptionally upregulated in response to Ras/ERK activation after TCR stimulation[21]
Summary
The sorting nexins (SNX) are proteins that regulate intracellular protein trafficking and endosomal signaling. We explored in more detail the consequences of SNX27 knockdown in DGKζ regulated T cell responses www.nature.com/scientificreports/. Both in T cell cultures and genetically modified Snx27−/− mice. Our results demonstrate that SNX27-silencing in Jurkat T cells results in Ras/ERK/AP-1 and NF-κB pathway hyperactivation, the two main DAG-regulated pathways in T lymphocytes. Such activation did not increase further upon DGKζ silencing suggesting that constitutive interaction of SNX27 with DGKζ sustains its function as a negative regulator of DAG metabolism. Our results extend the knowledge on SNX27 functions and suggest a previous unrecognized contribution on the coordinated regulation of DAG-based signals
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