Gui-Qiu Hu1, Pei-Xuan Song1, Wei Chen1, Shuai Qi1, Shui-Xing Yu1, Chong-Tao Du1, Xu-Ming Deng1, Hong-Sheng Ouyang1, Yong-Jun Yang2. 1. Key Laboratory of Zoonosis, Ministry of Education, College of Animal Medicine, Jilin University, Changchun 130062, China. 2. Key Laboratory of Zoonosis, Ministry of Education, College of Animal Medicine, Jilin University, Changchun 130062, China. Electronic address: youngjune@jlu.edu.cn.
Abstract
OBJECTIVE: Salmonella is known to evolve many mechanisms to avoid or delay inflammasome activation which remain largely unknown. In this study, we investigated whether the SopB protein critical to bacteria virulence capacity was an effector that involved in the regulation of inflammasome activation. METHODS: BMDMs from NLRC4-, NLRP3-, caspase-1/-11-, IFI16- and AIM2-deficient mice were pretreated with LPS, and subsequently stimulated with a series of SopB-related strains of Salmonella, inflammasome induced cell death, IL-1β secretion, cleaved caspase-1 production and ASC speckle formation were detected. RESULTS: We found that SopB could inhibit host IL-1β secretion, caspase-1 activation and inflammasome induced cell death using a series of SopB-related strains of Salmonella; however the reduction of IL-1β secretion was not dependent on sensor that contain PYD domain, such as NLRP3, AIM2 or IFI16, but dependent on NLRC4. Notably, SopB specifically prevented ASC oligomerization and the enzymatic activity of SopB was responsible for the inflammasome inhibition. Furthermore, inhibition of Akt signaling induced enhanced inflammasome activation. CONCLUSIONS: These results revealed a novel role in inhibition of NLRC4 inflammasome for Salmonella effector SopB.
OBJECTIVE: Salmonella is known to evolve many mechanisms to avoid or delay inflammasome activation which remain largely unknown. In this study, we investigated whether the SopB protein critical to bacteria virulence capacity was an effector that involved in the regulation of inflammasome activation. METHODS: BMDMs from NLRC4-, NLRP3-, caspase-1/-11-, IFI16- and AIM2-deficientmice were pretreated with LPS, and subsequently stimulated with a series of SopB-related strains of Salmonella, inflammasome induced cell death, IL-1β secretion, cleaved caspase-1 production and ASC speckle formation were detected. RESULTS: We found that SopB could inhibit host IL-1β secretion, caspase-1 activation and inflammasome induced cell death using a series of SopB-related strains of Salmonella; however the reduction of IL-1β secretion was not dependent on sensor that contain PYD domain, such as NLRP3, AIM2 or IFI16, but dependent on NLRC4. Notably, SopB specifically prevented ASC oligomerization and the enzymatic activity of SopB was responsible for the inflammasome inhibition. Furthermore, inhibition of Akt signaling induced enhanced inflammasome activation. CONCLUSIONS: These results revealed a novel role in inhibition of NLRC4 inflammasome for Salmonella effector SopB.
Authors: Glenn F W Walpole; Jonathan Pacheco; Neha Chauhan; Jonathan Clark; Karen E Anderson; Yazan M Abbas; Danielle Brabant-Kirwan; Fernando Montaño-Rendón; Zetao Liu; Hongxian Zhu; John H Brumell; Alexander Deiters; Len R Stephens; Phillip T Hawkins; Gerald R V Hammond; Sergio Grinstein; Gregory D Fairn Journal: Nat Cell Biol Date: 2022-04-28 Impact factor: 28.213