S-glutathionylation activates STIM1 and alters mitochondrial homeostasis

Abstract

Oxidant stress induces constitutive calcium entry by tacking glutathiones onto the Orai CRAC channel activator STIM1.

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

“…We previously demonstrated that oxidants promote InsP 3 R-and STIM1-dependent Ca 2+ signaling and cell injury in LPS-challenged cells (14,15). These findings led us to speculate that blockade of the Ca 2+ permeation pathway could prevent LPSinduced lung inflammation and vascular injury.…”

“…Studies by us and others have demonstrated that ROS can modulate cytosolic Ca 2+ signals generated through inositol 1,4,5-tris phosphate receptor (InsP 3 R) Ca 2+ release channels in ECs (15). More recently, we revealed that ROS can induce STIM-mediated Ca 2+ entry via Orai channels by activating STIM proteins through S-glutathionylation of an evolutionarily conserved N-terminal cysteine residue in the STIM1 protein (14). Although ROS overproduction is an established event upon LPS challenge, it remains unclear whether ROS/STIM1 signaling participates in TLR4-dependent EC activation, vascular permeability, and lung injury.…”

“…We previously showed that inhibition of STIM1/Orai1-mediated Ca 2+ entry prevented oxidative stress-induced cell death (14,28). Since endothelial STIM1 deficiency prevents LPSinduced vascular permeability, we examined pulmonary vascular Ca 2+ levels in situ.…”

“…STIM-induced Ca 2+ entry through Orai channels is now established as an essential Ca 2+ entry mechanism in non-excitable cell types (17)(18)(19)(20)(21)(22). STIM proteins are Ca 2+ store sensors and mediate the induction of cellular responses to a number of stress conditions, including elevated ROS, temperature changes, and hypoxia (14,19,23,24). Although oxidants and Ca 2+ are essential regulators of vascular signaling in pathophysiological settings including innate inflammation (5), precisely how ECs respond to LPS remained unclear.…”

“…Oxidants are implicated in modulating intracellular Ca 2+ release channels and Ca 2+ entry channels in the plasma membrane (14)(15)(16). STIM-induced Ca 2+ entry through Orai channels is now established as an essential Ca 2+ entry mechanism in non-excitable cell types (17)(18)(19)(20)(21)(22).…”