Lipopolysaccharides promoted S-nitrosylation and proteasomal degradation of liver kinase B1 in macrophage in vivo [Metabolism]

June 12th, 2015 by Liu, Z., Dai, X., Zhu, H., Zhang, M., Zou, M.-H.

Liver kinase B1 (LKB1) plays important roles in tumor suppression, energy metabolism, and recently, in innate immune responses. However, how LKB1 is regulated under physiological or pathological conditions is still unclear. Here we report that LKB1 protein but not mRNA was decreased in both lipopolysaccharide (LPS)-treated Raw264.7 cells and peritoneal macrophages isolated from LPS-challenged mice. Further LPS treatment promoted protein ubiquitination and degradation of LKB1. Pharmacological inhibition or gene silencing of inducible nitric oxide synthase (iNOS) abrogated LPS-induced LKB1 degradation, whereas exposure of Raw264.7 cells to S-nitrosoglutathione (GSNO), a nitric oxide (NO) donor, triggered LKB1 S-nitrosylation. Consistently, mutation of one cysteine (C430S) of LKB1 prevented LPS-induced S-nitrosylation, ubiquitination, and degradation. Moreover, S-nitrosylation and ubiquitination of LKB1 were confirmed in macrophages from LPS challenged mice in vivo. Co-administration of iNOS inhibitor SMT or proteasome inhibitor MG132 prevented LPS-induced LKB1 degradation and improved the survival rate. Finally, mice lacking LKB1 in macrophages had significantly lower survival rates in response to LPS challenge than wild type mice. Thus, we concluded that LKB1 was degraded by LPS treatment via S-nitrosylation-dependent proteasome pathways, and this had a protective role in LPS-induced septic shock.