Nitric oxide-GAPDH-Siah: a novel cell death cascade

Abstract

1. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an extremely abundant glycolytic enzyme, and exemplifies the class of proteins with multiple, seemingly unrelated functions. Recent studies indicate that it is a major intracellular messenger mediating apoptotic cell death. This paper reviews the GAPDH cell death cascade and discusses its clinical relevance. 2. A wide range of apoptotic stimuli activate NO formation, which S-nitrosylates GAPDH. The S-nitrosylation abolishes catalytic activity and confers upon GAPDH the ability to bind to Siah, an E3-ubiquitin-ligase, which translocates GAPDH to the nucleus. In the nucleus, GAPDH stabilizes the rapidly turning over Siah, enabling it to degrade selected target proteins and affect apoptosis. 3. The cytotoxicity of mutant Huntingtin (mHtt) requires nuclear translocation which appears to be mediated via a ternary complex of GAPDH-Siah-mHtt. The neuroprotective actions of the monoamine oxidase inhibitor R-(-)-deprenyl (deprenyl) reflect blockade of GAPDH-Siah binding. Thus, novel cytoprotective therapies may emerge from agents that prevent GAPDH-Siah binding.

Fig. 1.

Schematic diagram of NO-S-nitrosylation—GAPDH—Siah cell death cascade. NO causes S-nitrosylation of GAPDH at C150 (–SH). S-nitrosylation (–SNO) of GAPDH augments its binding to Siah. The nuclear localization signal of Siah mediates nuclear translocation of GAPDH. GAPDH stabilizes Siah facilitating its degradation of nuclear substrates, which leads to cell death. The alteration of GAPDH's shape from square to circular following S-nitrosylation designates its presumed conformational alteration that facilitates binding to Siah. The shape change in Siah following such binding denotes the stabilization by GAPDH of Siah.