Physical proximity and functional cooperation of glycoprotein 130 and glycoprotein VI in platelet membrane lipid rafts

Abstract

Objective:Clinical and laboratory studies have demonstrated that platelets become hyperactive and prothrombotic in conditions of inflammation. We have previously shown that the proinflammatory cytokine interleukin (IL)-6 forms a complex with soluble IL-6 receptor α (sIL-6Rα) to prime platelets for activation by subthreshold concentrations of collagen. Upon being stimulated with collagen, the transcription factor signal transducer and activator of transcription (STAT) 3 in platelets is phosphorylated and dimerized to act as a protein scaffold to facilitate the catalytic action between the kinase Syk and the substrate phospholipase Cγ2 (PLCγ2) in collagen-induced signaling. However, it remains unknown how collagen induces phosphorylation and dimerization of STAT3. Methods and results:We conducted complementary in vitro experiments to show that the IL-6 receptor subunit glycoprotein 130 (GP130) was in physical proximity to the collagen receptor glycoprotein VI (GPVI in membrane lipid rafts of platelets.This proximity allows collagen to induce STAT3 activation and dimerization, and the IL-6-sIL-6Rα complex to activate the kinase Syk and the substrate PLCγ2 in the GPVI signal pathway, resulting in an enhanced platelet response to collagen. Disrupting lipid rafts or blocking GP130-Janus tyrosine kinase (JAK)-STAT3 signaling abolished the cross-activation and reduced platelet reactivity to collagen.Conclusion: These results demonstrate cross-talk between collagen and IL-6 signal pathways. This cross-talk could potentially provide a novel mechanism for inflammation-induced platelet hyperactivity, so the IL-6-GP130-JAK-STAT3 pathway has been identified as a potential target to block this hyperactivity. K E Y W O R D Scytokine receptor GP130, membrane microdomain, platelet activation, platelet membrane glycoproteins, STAT3 transcription factor | 1501 HOUCK et al.

The palmitoyl acyltransferases ZDHHC5 and ZDHHC8 are uniquely present in DRG axons and control retrograde signaling via the Gp130/JAK/STAT3 pathway

“…However, one intriguing possibility is that palmitoylation targets Gp130 to lipid rafts, detergent-insoluble regions of the cell membrane to which palmitoyl-proteins often localize (68). Consistent with this possibility, several studies have detected Gp130 in lipid rafts (69)(70)(71)(72)(73)(74). Importantly, while Gp130 localization to lipid rafts appears to be constitutive in non-neuronal cells (69-71), a portion of Gp130 rapidly translocates to lipid rafts in a neuroblastoma cell line after CNTF treatment (71).…”

Platelet-leukocyte crosstalk in COVID-19: How might the reciprocal links between thrombotic events and inflammatory state affect treatment strategies and disease prognosis?

“…Fig. 2, section B depicted the cross-activations between IL-6, GP130, Janus tyrosine kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) and collagen receptor GPVI, that potentiate platelet activation through the Syk/phospholipaseCγ2 (PLCγ2) pathways [101,102].…”

Perspectives on Platelet Heterogeneity and Host Immune Response in Coronavirus Disease 2019 (COVID-19)

“…For instance, while platelets express the IL-6 receptor subunit IL-6Rβ (gp130), they do not express IL-6Rα and require exogenous addition of soluble sIL-6Rα to activate Jak/STAT and MAPK signaling ex vivo. 21 In vivo, however, platelets may respond to IL-6 through interactions with leukocytes that bring IL-6Rα in close proximity to platelets in a manner related to models of platelet-leukocyte interactions in COVID-19 proposed by Merad and Martin, 22 and that may be targeted by agents such as tocilizumab. 23 Such mechanisms are supported by recent studies demonstrating upregulated MAPK signaling, and increased platelet reactivity and platelet-leukocyte aggregation in COVID-19 patients.…”