TCR activation stimulates regulated intramembrane proteolysis of L-selectin by presenilin 1 and localized proteasomal degradation of the cytoplasmic tail
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Biochemistry paper on regulated intramembrane proteolysis of L-selectin in T cells; the object is cell signalling.
The study investigates molecular mechanisms of L-selectin processing in T cells.
Cell/molecular immunology of L-selectin proteolysis after TCR activation.
Résumé
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 signaling downstream of L-selectin is not known. In T cells, there is substantial overlap between signaling downstream of L-selectin and the T-cell receptor (TCR). Cross-linking of L-selectin stimulates phosphorylation of the cytoplasmic tail and forward signaling via the nonreceptor 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 ECD. To further understand the role of L-selectin in T cell biology, we used T cells to dissect the cross-talk between L-selectin and physiological TCR activation. We used a combination of imaging flow cytometry and biochemistry to localize L-selectin ECD and intracellular domain (ICD) following engagement of the TCR. We show that following A Metalloproteinase And Disintegrin (ADAM) 17-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 costimulation by L-selectin.
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La notice
- Revue
- Journal of Biological Chemistry
- Thématique
- Cell Adhesion Molecules Research
- Domaine
- Medicine
- Établissements canadiens
- Institute of Infection and Immunity
- Organismes subventionnaires
- Erasmus+Medical Research CouncilDirectorate for Biological SciencesBiotechnology and Biological Sciences Research CouncilCardiff UniversityEuropean Regional Development FundKing's College LondonLlywodraeth CymruBritish Heart FoundationSaudi Arabia Cultural Bureau in LondonWellcome Trust
- Mots-clés
- EctodomainCell biologyT-cell receptorBiologyJurkat cellsPhosphorylationCytoplasmT cellReceptorBiochemistryImmune systemImmunology
- Résumé présent dans OpenAlex
- oui