SHARPIN at the nexus of integrin, immune, and inflammatory signaling in human platelets

Proceedings of the National Academy of Sciences of the United States of America
Ana Kasirer-FriedeS J Shattil

Abstract

Platelets mediate primary hemostasis, and recent work has emphasized platelet participation in immunity and inflammation. The function of the platelet-specific integrin αIIbβ3 as a fibrinogen receptor in hemostasis is well defined, but the roles of αIIbβ3 or integrin-associated proteins in nonhemostatic platelet functions are poorly understood. Here we show that human platelets express the integrin-associated protein SHARPIN with functional consequences. In leukocytes, SHARPIN interacts with integrin α cytoplasmic tails, and it is also an obligate member of the linear ubiquitin chain assembly complex (LUBAC), which mediates Met1 linear ubiquitination of proteins leading to canonical NF-κB activation. SHARPIN interacted with αIIb in pull-down and coimmunoprecipitation assays. SHARPIN was partially localized, as was αIIbβ3, at platelet edges, and thrombin stimulation induced more central SHARPIN localization. SHARPIN also coimmunoprecipitated from platelets with the two other proteins comprising LUBAC, the E3 ligase HOIP and HOIL-1. Platelet stimulation with thrombin or inflammatory agonists, including lipopolysaccharide or soluble CD40 ligand (sCD40L), induced Met1 linear ubiquitination of the NF-κB pathway protein NEMO and seri...Continue Reading

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Citations

Jan 4, 2020·Journal of Thrombosis and Haemostasis : JTH·Lisa ColbergUlrike Seifert
Aug 21, 2019·Cell Communication and Signaling : CCS·Juan GaoYan-Qing Ma
Dec 2, 2020·Animals : an Open Access Journal From MDPI·Shan LinDongxiao Sun
Jan 6, 2021·Cellular and Molecular Neurobiology·Dhanya KrishnanSrinivas Gopala
Sep 14, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Zelin TianGaosong Wu
Aug 27, 2021·Frontiers in Immunology·Laura BarnabeiRobert Weil

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