S-nitrosylated NEDD4 exacerbates gouty arthritis by upregulating NOD1 to induce pyroptosis.

Abstract

Gouty arthritis (GA) is a common inflammatory disease which has no effective treatments. Pyroptosis has been reported to exacerbate the progression of GA. We aimed to explore the molecular mechanism by which S-nitrosylated NEDD4 accelerates GA progression by regulating pyroptosis. In our study, we found NOD1 knockdown inhibited pyroptosis and reduced c-Caspase-1, NLRP3, ASC, and GSDMD-N expression, IL-1β and IL-18 levels, and XOD activity in GA in vivo and in vitro. In addition, NOD1 knockdown alleviated inflammatory symptoms of joint tissues in GA mice model. Moreover, downregulation of NEDD4 caused by S-nitrosylation modification at C365 site upregulated NOD1 expression by reducing ubiquitination and degradation of NOD1. Furthermore, iNOS promoted NOD1 expression by mediating S-nitrosylation of NEDD4 thereby inducing GA in vitro. In conclusion, S-nitrosylation of NEDD4 promoted NLRP3-mediated pyroptosis by upregulating NOD1 expression, which ultimately accelerated the development of GA. We are the first to report the expression patterns of NEDD4 and NOD1 in GA, and demonstrated firstly that S-nitrosylation of NEDD4 inhibited ubiquitination-mediated degradation of NOD1, thereby modulating pyroptosis in GA. By elucidating how S-nitrosylation of NEDD4 orchestrates NOD1-mediated pyroptosis, this work opens avenues for developing first-in-class therapies for GA.