Regulation of apoptosis through cysteine oxidation: implications for fibrotic lung disease

Abstract

Tissue fibrosis is believed to be a manifestation of dysregulated repair following injury, in association with impaired reepithelialization, and aberrant myofibroblast activation and proliferation. Numerous pathways have been linked to the pathogenesis of fibrotic lung disease, including the death receptor Fas, which contributes to apoptosis of lung epithelial cells. A redox imbalance also has been implicated in disease pathogenesis, although mechanistic details whereby oxidative changes intersect with profibrotic signaling pathways remain elusive. Oxidation of cysteines in proteins, such as Sglutathionylation (PSSG), is known to act as a regulatory event that affects protein function. This manuscript will discuss evidence that S-glutathionylation regulates death receptor induced apoptosis, and the potential implications for cysteine oxidations in the pathogenesis of in fibrotic lung disease.

Oxidative Processing of Latent Fas in the Endoplasmic Reticulum Controls the Strength of Apoptosis

“…Lung fibrosis is believed to be a manifestation of dysregulated repair following injury, in association with impaired reepithelialization and aberrant myofibroblast activation and proliferation (23). Numerous pathways have been linked to the pathogenesis of fibrotic lung disease, including Fas (4,49), which contributes to apoptosis of lung epithelial cells.…”

Glutathione and redox signaling in substance abuse

“…While S -glutathionylation of Prdx6 is protective, the second protein has been identified as a GSTP target amplifies apoptosis. The death receptor Fas is S -glutathionylated on Cys294 (Fas-SSG) prior to the onset of apoptosis [14,17]. Fas is a member of the tumor necrosis receptor superfamily such that the binding of ligand leads to the downstream activation caspase 8- or 10- mediated apoptosis.…”

N-Acetylcysteine Modulates the Cytotoxic Effects of Paclitaxel

“…It has been demonstrated that depending on the degree of intracellular oxidative stress, which depends on the redox balance between ROS generation and antioxidant mechanisms, caspases can be activated or inhibited [29]. Oxidation of cysteines in proteins is known to act as a regulatory event that affects protein function [34]. In our study, altering the intracellular concentration of NAC might shed light on the relationship among paclitaxel-induced changes in the susceptibility of caspase cysteines to redox modification, caspase activities, and apoptosis.…”