Downregulation of PIK3IP1/TrIP on T cells is controlled by TCR signal strength, PKC and metalloprotease-mediated cleavage.

Autor:	Murter BM; Dept. of Immunology, University of Pittsburgh, Pittsburgh PA, USA.; Graduate Program in Microbiology and Immunology, University of Pittsburgh, Pittsburgh PA, USA., Robinson SC; Dept. of Immunology, University of Pittsburgh, Pittsburgh PA, USA., Banerjee H; Dept. of Immunology, University of Pittsburgh, Pittsburgh PA, USA., Lau L; Dept. of Immunology, University of Pittsburgh, Pittsburgh PA, USA.; Graduate Program in Microbiology and Immunology, University of Pittsburgh, Pittsburgh PA, USA., Uche UU; Dept. of Immunology, University of Pittsburgh, Pittsburgh PA, USA., Szymczak-Workman AL; Dept. of Immunology, University of Pittsburgh, Pittsburgh PA, USA., Kane LP; Dept. of Immunology, University of Pittsburgh, Pittsburgh PA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 21. Date of Electronic Publication: 2024 Oct 21.
DOI:	10.1101/2024.04.29.591680
Abstrakt:	The protein known as PI3K-interacting protein (PIK3IP1), or transmembrane inhibitor of PI3K (TrIP), is highly expressed by T cells and can modulate PI3K activity in these cells. Several studies have also revealed that TrIP is rapidly downregulated following T cell activation. However, it is unclear as to how this downregulation is controlled. Using a novel monoclonal antibody that robustly stains cell-surface TrIP, we demonstrate that TrIP is lost from the surface of activated T cells in a manner dependent on the strength of signaling through the T cell receptor (TCR) and specific downstream signaling pathways, in particular classical PKC isoforms. TrIP expression returns by 24 hours after stimulation, suggesting that it may play a role in resetting TCR signaling at later time points. We also provide evidence that ADAM family proteases are required for both constitutive and stimulation-induced downregulation of TrIP in T cells. Finally, by expressing truncated forms of TrIP in cells, we identify the region in the extracellular stalk domain of TrIP that is targeted for proteolytic cleavage. Competing Interests: Conflict of Interest The authors declare that they have no conflicts of interest relevant to the contents of this article.
Databáze:	MEDLINE
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