Nitric oxide (NO), a simple molecule, plays important roles in virtually every biological system. Whereas NO synthesis and its regulation have been studied extensively, deactivation of NO, a step critical to the control of NO bioactivity, is much less studied or understood. NO regulates many cellular functions through protein S-nitrosylation, the covalent modification of cysteine thiols. Through the study of S-nitroso-glutathione reductase (GSNOR), the key protein for inactivating S-nitrosylation, we have demonstrated that S-nitrosylation and its deactivation exert critical functions in systematic inflammation (Cell 116:617), asthma (Science 308:1618), cancer (Science TM 2:19ra13), and many other physiological and pathological conditions.
GSNOR and asthma. Our previous work established that, in mammals as well as in simple eukaryotes, GSNOR is essential for regulation of both S-nitrosylated peptides and proteins (Nature 410:490; Cell 116:617). Using genetically engineered GSNOR-deficient (GSNOR-/-) mice, we demonstrated that GSNOR-regulated S-nitrosylation is a critical determinant of airway responsiveness in an animal model of asthma (Science 308:1618). We are investigating further NO-related mechanisms important for the control of airway reactivity.
GSNOR and carcinogenesis. NO is implicated in tumorigenesis by much circumstantial evidence, but little is known definitively about the mechanisms through which endogenous NO might regulate the behavior of pre-cancerous or cancerous cells. Using GSNOR-/- mice we showed that dysregulated S-nitrosylation from GSNOR deficiency inactivates a key DNA repair system and promotes liver cancer (Science Translational Medicine 2:19ra13, 2010). Investigation is underway to expend the findings and to further elucidate molecular mechanisms.
New pathways in NO deactivation. We have demonstrated that GSNOR and flavohemoglobin, the major NO-consuming enzyme, operate together to regulate NO bioactivities and to protect against NO-related toxicity in the yeast Saccharomyces cerevisia (PNAS 97:4672; Nature 410:490). We are employing the yeast model to elucidate the roles of additional, novel genes that are required for protection against NO-related toxicity. Homologue proteins are also investigated in animals.
Liu L, Hausladen A, Zeng M, Loretta Que, Heitman J, Stamler JS (2001). A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans. Nature 410:490-494.
Liu L, Yan Y, Zeng M, Zhang J, Hanes MA, Ahearn G, McMahon TJ, Dickfeld T, Marshall HE, Que LG, Stamler JS (2004). Essential roles of S-nitrosothiols in vascular homeostasis and endotoxic shock. Cell 116:617-628.
Que LG, Liu L, Yan Y, Whitehead GS, Gavett SH, Schwartz DA, Stamler JS (2005). Protection from experimental asthma by an endogenous bronchodilator. Science 308:1618-1621.
Wei W, Li B, Hanes MA, Kakar S, Chen X, Liu L (2010). Deficiency of S-Nitrosoglutathione Reductase Impairs DNA Repair and Promotes Hepatocarcinogenesis. Science Translational Medicine 2: 19ra13.