Protein S-nitrosylation: role for nitric oxide signaling in neuronal death

Abstract

Background: One of the signaling mechanisms mediated by nitric oxide (NO) is through S-nitrosylation, the reversible redox-based modification of cysteine residues, on target proteins that regulate a myriad of physiological and pathophysiological processes. In particular, an increasing number of studies have identified important roles for S-nitrosylation in regulating cell death.

Scope of review: The present review focuses on different targets and functional consequences associated with nitric oxide and protein S-nitrosylation during neuronal cell death.

Major conclusions: S-Nitrosylation exhibits double-edged effects dependent on the levels, spatiotemporal distribution, and origins of NO in the brain: in general Snitrosylation resulting from the basal low level of NO in cells exerts anti-cell death effects, whereas S-nitrosylation elicited by induced NO upon stressed conditions is implicated in pro-cell death effects.

General significance: Dysregulated protein S-nitrosylation is implicated in the pathogenesis of several diseases including degenerative diseases of the central nervous system (CNS). Elucidating specific targets of S-nitrosylation as well as their regulatory mechanisms may aid in the development of therapeutic intervention in a wide range of brain diseases.

Fig. 1. Anti-cell death mechanism associated with NO and protein S-nitrosylation: caspase inactivation and anti-apoptotic effects

Under basal conditions, nitric oxide synthase (NOS) activity is low and basal levels of nitric oxide (NO) contribute to anti-cell death mechanisms. For example, low dose of NO, S-nitrosylates (SNO) procaspases/caspases and inhibits their activities.

Fig. 2. Pro-cell death mechanisms associated with NO and protein S-nitrosylation: caspase activation and nuclear translocation of GAPDH

Under stressed condition, activation of thioredoxin (Trx)/Trx reductase (TrxR) system (specifically in mitochondria) leads to procaspase3 denitrosylation, resulting in caspase-3 activation and apoptosis. In addition, NO inactivates the E3 ligase activity of X-linked inhibitor of apoptosis (XIAP) via S-nitrosylation (SNO), thus stabilizing caspases. Excessive nitrosative stress stimulates the formation of NO, which S-nitrosylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH) enabling it to bind and stabilize Siah. Siah’s nuclear localization signal mediates nuclear translocation of the GAPDH-Siah complex. Stabilized Siah in the protein complex with S-nitrosylated GAPDH facilitate degradation of nuclear co-repressor N-CoR. Nuclear translocated GAPDH is further acetylated at by the histone acetyltransferase p300 via direct protein interaction, which in turn stimulates the catalytic activity of p300. Both of these mechanisms by the nuclear GAPDH-Siah complex regulate gene expression, which results in cellular dysfunction/cell death/apoptosis.

Fig. 3. GOSPEL as the regulator of the cell death mechanism associated with GAPDH nuclear translocation

GOSPEL (GAPDH’s competitor Of Siah Protein Enhances Life) was recently identified as a physiological inhibitor against GAPDH-Siah binding. At the initial phase of nitrosative stress when NO levels are low, S-nitrosylation (SNO) of GOSPEL augments binding of GOSPEL and GAPDH, competing with Siah for binding to GAPDH, leading to retention of GAPDH in the cytosol and preventing its nuclear translocation and inhibiting cell death.