Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan

Andrea J. Wolf, Christopher N. Reyes, Wenbin Liang, Courtney Becker, Kenichi Shimada, Matthew L. Wheeler, Hee Cheol Cho, Narcis I. Popescu, K. Mark Coggeshall,  Moshe Arditi and David M. Underhill

Speaker: Zhong-Hong Wu (吳忠鴻)                                             Time: 13:00~14:00, Nov. 8, 2017

Commentator: Pei-Jane Tsai, Ph.D. (蔡佩珍老師)                      Place: Room 601

Abstract:

        Macrophages and dendritic cells play essential roles in initiating inflammation by releasing cytokines and chemokines in response to pathogen-associated molecular patterns (PAMPs) detected by innate immune receptors. Degradation of Gram-positive bacterial cell wall peptidoglycan (PGN) in macrophage and dendritic cell phagosomes leads to activation of the NLRP3 inflammasome, a cytosolic complex that regulates processing and secretion of interleukin (IL)-1b and IL-18. IL-1b and IL-18 play essential roles in controlling bacterial infections, but the mechanism by which NLRP3 is activated by PGN is not known. In this study, the authors find out that PGN-induced NLRP3 inflammasome activation is independent of potassium efflux and pyroptosis. PGN inhibit hexokinase and induce its dissociation from mitochondria, and N-acetylglucosamine (NAG) is the minimal inflammasome-activating component of PGN. Hexokinase dissociation from mitochondria is sufficient to trigger NLRP3 inflammasome activation and IL-1b production. In addition, the authors observe that metabolic perturbations affecting hexokinase activate the NLRP3 Inflammasome. Glycolytic inhibitors and metabolic conditions affecting hexokinase function and localization induce inflammasome activation. These data suggest an intriguing relationship between cellular metabolism and inflammatory signaling.

References:

1.      Haitao Guo1, Justin B Callaway and Jenny P-Y Ting (2015). Inflammasomes: mechanism of action, role in disease, and therapeutics. Nature Medicine 21, 677-687.

Mohamed Lamkanfi and Vishva M. Dixit (2014). Mechanisms and Functions of Inflammasomes. Cell 157, 1013-1022.