Reactive Oxygen Species-Induced Actin Glutathionylation Controls Actin Dynamics in Neutrophils

Abstract

Summary The regulation of actin dynamics is pivotal for cellular processes such as cell adhesion, migration, and phagocytosis, and thus is crucial for neutrophils to fulfill their roles in innate immunity. Many factors have been implicated in signal-induced actin polymerization, however the essential nature of the potential negative modulators are still poorly understood. Here we report that NADPH oxidase-dependent physiologically generated reactive oxygen species (ROS) negatively regulate actin polymerization in stimulated neutrophils via driving reversible actin glutathionylation. Disruption of glutaredoxin 1 (Grx1), an enzyme that catalyzes actin deglutathionylation, increased actin glutathionylation, attenuated actin polymerization, and consequently impaired neutrophil polarization, chemotaxis, adhesion, and phagocytosis. Consistently, Grx1-deficient murine neutrophils showed impaired in vivo recruitment to sites of inflammation and reduced bactericidal capability. Together, these results present a physiological role for glutaredoxin and ROS- induced reversible actin glutathionylation in regulation of actin dynamics in neutrophils.

S-glutathionylation: relevance in diabetes and potential role as a biomarker

“…A recent report describes how stimulated neutrophils present deglutathionylated actin and associated polymerization, neutrophil polarization, chemotaxis, adhesion and phagocytosis. When Grx1 expression was silenced in cells or ablated in a murine model, actin was S-glutathionylated, neutrophil recruitment to sites of inflammation was impaired, and the bactericidal capability was reduced (Sakai et al, 2012). All these reports highlight the role of protein-S-glutathionylation in the alteration of neutrophil function and might be responsible for neutrophil dysfunction in diabetic disease.…”

Proteinase 3–dependent caspase-3 cleavage modulates neutrophil death and inflammation

“…Superoxide production. Measurement of ROS in stimulated neutrophils was conducted as previously described (49,50). Briefly, murine neutrophils were resuspended at a density of 1 × 10 7 /ml in HBSS and kept on ice until use.…”

Contribution of NADPH-oxidase to the establishment of hippocampal neuronal polarity in culture

“…Thus, Rac1 and Cdc42, members of the small GTPase Rho family, promote neuronal polarization and axonal growth (Gonzalez-Billault et al, 2012). Oxidation of actin decreases its ability to polymerize (Hung et al, 2011(Hung et al, , 2010Sakai et al, 2012;Terman and Kashina, 2013). However, inhibition of NOX reduces both the F-actin content at the growth cone and the retrograde actin flow in neurons, suggesting a crosslink between NOX and actin dynamics (Munnamalai and Suter, 2009;Munnamalai et al, 2014).…”