TCR activation stimulates regulated intramembrane proteolysis of L-selectin by presenilin 1 and localized proteasomal degradation of the cytoplasmic tail

Moon, Owen R., Newman, Andrew C., Alanazi, Abdullah S., Wehenkel, Sophie C., Gawel-Bęben, Katarzyna, Ivetic, Aleksandar, Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Knauper, Vera ORCID: https://orcid.org/0000-0002-3965-9924 and Ager, Ann ORCID: https://orcid.org/0000-0002-5763-8908 2025. TCR activation stimulates regulated intramembrane proteolysis of L-selectin by presenilin 1 and localized proteasomal degradation of the cytoplasmic tail. Journal of Biological Chemistry , 110473. 10.1016/j.jbc.2025.110473

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Abstract

Leucocyte (L)-selectin is essential for mounting protective immunity to pathogens. As well as regulating leucocyte recruitment, it also regulates their activation and differentiation inside tissues thereby shaping local immune responses. The biochemical signals that regulate these diverse functions of L-selectin are poorly understood. Leucocyte activation induces proteolytic shedding of L-selectin ectodomain (ECD) but the impact of ECD shedding on signalling downstream of L-selectin is not known. In T cells there is substantial overlap between signalling downstream of L-selectin and the TCR. Cross-linking of L-selectin stimulates phosphorylation of the cytoplasmic tail and forward signalling via the non-receptor tyrosine kinases Lck and Zap70. Cross-linking of TCR induces phosphorylation-dependent binding of PKC isozymes to L-selectin cytoplasmic tail and PKCα dependent shedding of ectodomain (ECD). To further understand the role of L-selectin in T cell biology, we used T cells to dissect the crosstalk between L-selectin and physiological TCR activation. We used a combination of imaging flow cytometry and biochemistry to localise L-selectin ECD and intracellular domain (ICD) following engagement of the TCR. We show that following ADAM17 dependent ECD shedding from the plasma membrane, the ICD containing transmembrane retained fragment undergoes intramembrane proteolysis by PS1 containing γ-secretase. Subsequent degradation of L-selectin ICD occurs via the proteasome in the vicinity of the plasma membrane. Regulated intramembrane proteolysis and rapid degradation of L-selectin ICD following TCR activation suggests that the turnover of L-selectin cytoplasmic tail is an important regulator of T cell co-stimulation by L-selectin.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Dentistry Schools > Medicine Research Institutes & Centres > Systems Immunity Research Institute (SIURI)
Publisher:	Elsevier
ISSN:	0021-9258
Date of First Compliant Deposit:	22 July 2025
Date of Acceptance:	20 June 2025
Last Modified:	22 Jul 2025 09:15
URI:	https://orca.cardiff.ac.uk/id/eprint/179950

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