8-Nitro-cGMP: A Novel Protein-Reactive cNMP and Its Emerging Roles in Autophagy

Abstract

Nitric oxide (NO) raises the intracellular 3',5'-cyclic guanosine monophosphate (cGMP) level through the activation of soluble guanylate cyclase and, in the presence of reactive oxygen species (ROS), reacts with biomolecules to produce nitrated cGMP derivatives. 8-Nitro-cGMP was the first endogenous cGMP derivative discovered in mammalian cells (2007) and was later found in plant cells. Among the six nitrogen atoms in this molecule, the one in the nitro group (NO) comes from NO. This chapter asserts that this newly found cGMP is undoubtedly one of the major physiological cNMPs. Multiple studies suggest that its intracellular abundance might exceed that of unmodified cGMP. The characteristic chemical feature of 8-nitro-cGMP is its ability to modify proteinous cysteine residues via a stable sulfide bond. In this posttranslational modification, the nitro group is detached from the guanine base. This modification, termed "protein S-guanylation," is known to regulate the physiological functions of several important proteins. Furthermore, 8-nitro-cGMP participates in the regulation of autophagy. For example, in antibacterial autophagy (xenophagy), S-guanylation accumulates around invading bacterial cells and functions as a "tag" for subsequent clearance of the organism via ubiquitin modifications. This finding suggests the existence of a system for recognizing the cGMP structure on proteins. Autophagy induction by 8-nitro-cGMP is mechanistically distinct from the well-described starvation-induced autophagy and is independent of the action of mTOR, the master regulator of canonical autophagy.

Gasotransmitters in pregnancy: from conception to uterine involution†

“…NFκB persulfidation reduces TNFαstimulated apoptosis [90], while ATP-gated K + (K ATP ) and BK Ca channel persulfidation hyperpolarizes cell membranes [92]. 8-HS-cGMP forms by persulfidation of 8-nitro-cGMP, a cGMP derivative that promotes autophagy and oncogenesis [93]. Compared with cGMP, 8-HS-cGMP resists degradation by PDE5.…”

Developing Polysulfide-Sensitive GFPs for Real-Time Analysis of Polysulfides in Live Cells and Subcellular Organelles

“…10 As nucleophiles, they can scavenge reactive oxygen species (ROS) and react with the autophagy regulator 8-NO 2 -cGMP. 3,11,12 Higher cellular levels of polysulfides should lead to more protein sulfhydration and confer cells with more resistance to oxidative stress.…”

“…As electrophiles, they can transfer sulfur atoms (the sulfane sulfur, S 0 ) to protein thiols to generate protein persulfides (protein–SSH), a process termed protein S-sulfhydration. − According to a recent report, more than 40% of intracellular proteins are S-sulfhydrated . As nucleophiles, they can scavenge reactive oxygen species (ROS) and react with the autophagy regulator 8-NO 2 -cGMP. ,, Higher cellular levels of polysulfides should lead to more protein sulfhydration and confer cells with more resistance to oxidative stress.…”

The first line of defence: insights into mechanisms and relevance of phagocytosis in epithelial cells

“…Consequently, autophagy is enhanced [ 80 ]. NO + induces cGMP nitration to generate the endogenous xenophagy enhancer 8-nitro-cGMP [ 81 ]. This molecule modifies cysteine residues of proteins (S-guanylation) on the surface of cytosolic bacteria.…”