Skap2 is required for β2 integrin–mediated neutrophil recruitment and functions

Abstract

Boras et al. demonstrate that Skap2, via interaction with WASp, regulates actin polymerization and binding of talin-1 and kindlin-3 to the β2 integrin, thereby being indispensable for β2 integrin activation and neutrophil recruitment.

Talin1 Methylation Is Required for Neutrophil Infiltration and Lipopolysaccharide-Induced Lethality

“…Kank2 can also bind talin in the vicinity of its actin-binding site 2 (ABS2), keeping it in an activated state at focal adhesion (FA) belts while simultaneously reducing F-actin binding and traction force transmission to promote FA disassembly (17) or the formation of fibrillar adhesions (18,19). Moreover, Skap2 can form a complex with Wiskott-Aldrich syndrome protein (WASp) to promote global actin polymerization and the binding of talin1 and kindlin3 to integrin, thereby regulating integrin activation and neutrophil recruitment in vivo (20). It has also been shown that negatively charged phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] at FAs may enable the activation of talin (13).…”

Phosphoinositides: multipurpose cellular lipids with emerging roles in cell death

“…NET release forms a novel host defense mechanism against invading microbial pathogens. Though the execution and regulation of NETosis are still not fully understood, it is emerging that PI(3,4,5)P 3 -mediated recruitment and activation of NETotic effectors, including Src kinase-associated phosphoprotein-2 (Skap2), WASPs and integrins [88]. While initial studies showed that Skap2 adopts an autoinhibitory conformation in steady-state neutrophils, upon stimulation, interactions with PI(3,4,5)P 3 via its PH domain induces a switch to the active conformation [89].…”

“…While initial studies showed that Skap2 adopts an autoinhibitory conformation in steady-state neutrophils, upon stimulation, interactions with PI(3,4,5)P 3 via its PH domain induces a switch to the active conformation [89]. Then, Skap2 can form a complex with WASPs and translocate to the inner leaflet of the plasma membrane, leading to the downstream activation of integrins [88,89]. In Skap2 −/− neutrophils reconstituted with a Skap2 R140M mutant, which has been previously shown to impair PI (3,4,5)P 3 binding to the PH domain [89], both Skap2 and WASPs are unable to translocate to the plasma membrane and, consequentially, resulting in failed NETosis.…”

STIMulation of signaling in neutrophils

“…6 However, under distinct conditions like ischemia-reperfusion injury or sterile inflammation, recruited neutrophils and their elicited immune reactions can also destroy host cells and tissues, leading to severe complications. 7 To keep the balance between positive and negative effects, neutrophil recruitment as well as effector functions have to be tightly controlled. 8 Mutations or deficiencies in the 2 STIM molecules exhibit distinct phenotypes.…”