Regulation of Unfolded Protein Response via Protein S-nitrosylation

Nitric oxide (NO) plays a pivotal function in neurotransmission, vasodilation, proliferation, and apoptosis in various types of cells via protein S-nitrosylation. Previously we demonstrated that protein disulfide isomerase (PDI) is S-nitrosylated in brains manifesting sporadic neurodegenerative diseases. This modification results in dysfunction of its enzymatic activity and consequently the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER). The aim of this study was to clarify the detailed function of NO on unfolded protein response (UPR) branches. We here found that the ER stress sensor IRE1 alpha is S-nitrosylated. Interestingly, NO specifically abrogates ribonuclease activity, but not oligomerization or autophosphorylation of IRE1 alpha. Site-directed mutagenesis revealed that Cys 931 and Cys951 in IRE1 are targets for S-nitrosylation. These mutants expressing in IRE1 alpha knockout MEF showed a resistant role to the inhibition of nuclease activity by NO. Thus, we elucidated the effects of S-nitrosylation on ER stress sensors that mediate the UPR, and thus contribute to cell death pathways.