Redox-dependent thiol modifications: implications for the release of extracellular vesicles

Abstract

Extracellular vesicles (EVs), including microvesicles and exosomes, are emerging as important regulators of homeostasis and pathophysiology. During pro-inflammatory and pro-oxidant conditions, EV release is induced. As EVs released under such conditions often exert pro-inflammatory and procoagulant effects, they may actively promote the pathogenesis of chronic diseases. There is evidence that thiol group-containing antioxidants can prevent EV induction by pro-inflammatory and oxidative stimuli, likely by protecting protein thiols of the EV-secreting cells from oxidation. As the redox state of protein thiols greatly impacts three-dimensional protein structure and, consequently, function, redox modifications of protein thiols may directly modulate EV release in response to changes in the cell’s redox environment. In this review article, we discuss targets of redox-dependent thiol modifications that are known or expected to be involved in the regulation of EV release, namely redox-sensitive calcium channels, N-ethylmaleimide sensitive factor, protein disulfide isomerase, phospholipid flippases, actin filaments, calpains and cell surface-exposed thiols. Thiol protection is proposed as a strategy for preventing detrimental changes in EV signaling in response to inflammation and oxidative stress. Identification of the thiol-containing proteins that modulate EV release in pro-oxidant environments could provide a rationale for broad application of thiol group-containing antioxidants in chronic inflammatory diseases.

The Potential Roles of Extracellular Vesicles in Cigarette Smoke‐Associated Diseases

“…EVs, induced under oxidative stress conditions, exhibit proinflammatory and prothrombotic effects which contribute to the pathogenesis of chronic diseases. The thiol-reactive compounds like acrolein, an endogenous inflammatory metabolite, contributed to exosome release by CS by reacting with cell surface thiols in the airway epithelial cells [ 18 , 20 , 21 ]. EV release was also enhanced with plasma membrane blebbing in response to thiol-reactive RCS (reactive carbonyl species) and ROS (reactive oxygen species).…”

“…Moreover, EV shedding by thiol modifications protected the secreting cell against oxidative damage; however, at the same time, it induced a proinflammatory and prothrombotic state of the cells. However, both exosome release by CS [ 21 ] and the oxidation of protein thiols of the EV-secreting cells [ 18 ] were blocked by thiol antioxidants like N-acetyl cysteine (NAC) and glutathione S-transferase (GSH). These data clearly indicate that CS-induced EV release could be suppressed by thiol antioxidants.…”

“…Exposure to cigarette smoke (CS)/extract (CSE) stimulated EVs and exosome release into the serum, saliva, urine of smokers/ex-smokers, and cancer patients, as well as from various cultured cells [ 10 , 11 ]. Moreover, exosome secretion by CS led to several biochemical and cellular processes, including angiogenesis [ 12 ], endothelial dysfunction [ 8 ], and tissue remodeling [ 13 ], as well as proinflammatory [ 14 ] and prothrombotic effects [ 15 , 16 ], promoting the pathogenesis of CS-related chronic diseases as categorized by Benedikter et al [ 12 , 17 , 18 ].…”

“…Recently, a number of studies have suggested that oxidative stress affects the release of EVs in various cell types and human samples [ 15 , 16 , 19 ]. Although the mechanism underlying exosome release by cigarette smoke is not fully elucidated, redox-dependent thiol modification seems to be a plausible explanation for the exosome release under stress condition by CS [ 18 ]. The pathophysiological and cellular processes implicated in cigarette smoke-triggered exosome release are suggested to be the potential mechanisms that account for cigarette smoke-induced pathogenesis [ 6 ].…”

Proteína dissulfeto isomerase plasmática: detecção e correlação com assinaturas proteômicas ligadas a distintos fenótipos endoteliais em indivíduos saudáveis

“…Third, lipoprotein oxidation and formation of oxidized lipid products is believed to be a major trigger of early atheroma development, as well as of later complications [170,171]. A general framework for the mechanisms whereby extracellular redox processes affect intracellular redox processes and, conversely, how intracellular processes contribute to plasma redox milieu suggests roles for the oxidation of specific proteins [172], as well as for secreted microparticles [172], which are highly thiol redox-modulated [173] and circulating miRNAs [174]. Along these lines, the involvement of plasma thiol redox pools in atherosclerosis can be more directly linked to effects in: (i) lipoprotein oxidation; (ii) inflammatory responses of circulating blood elements; (iii) cell membrane oxidative damage; (iv) thrombosis; (v) modification of plasma and extracellular matrix proteins, and (vi) signaling events in endothelial cells.…”