Phosphorylation of ULK1 By p38 MAPK As A Functional Switch In Promoting Microglial Inflammatory Response


Identification: Mao, Zixu


Description

Phosphorylation of ULK1 By p38 MAPK As A Functional Switch In Promoting Microglial Inflammatory Response
 
Zixu Mao1, *, Yingli He1, 2, 3, Hua She1, 2, Ting Zhang1, 4, Haidong Xu1, 2, and Yingren Zhao3
 
1Department of Pharmacology and 2Department of Neurology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322 USA
 
3The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi 710061, People's Republic of China
 
4Key Laboratory of Environmental Medicine Engineering, School of Public Health, Southeast University, Nanjing, Jiangsu 210009, People's Republic of China
 
Correspondence to Zixu Mao: zmao@emory.edu; Yingren Zhao: zhaoyingren@mail.xjtu.edu.cn
 
Abstract
Inflammation and autophagy are two highly intertwined cellular processes. The relationship between inflammation and autophagy is quite complex and reciprocal. There is evidence that autophagy inhibits inflammation. However, the mechanisms that relieve this autophagy-mediated inhibition to permit an inflammatory response remain poorly understood. Our recent studies define a mechanism by which inflammatory stimulus releases the brake exerted by autophagy in microglial cells to trigger a robust inflammatory response. Using LPS as a model agent, we showed that proinflammatory signal leads to a p38α MAPK-dependent phosphorylation of ULK1 in microglial cells, which inhibits ULK1 kinase activity, prevents it from binding to the downstream effector ATG13 in the initiation complex, and reduces autophagy in microglia. This appears to be required for LPS-induced morphological changes and the production of IL-1β by primary microglia in vitro and in the brain. Furthermore, inhibition of ULK1 alone was sufficient to promote an inflammatory response in the absence of overt inflammatory stimulation. Interestingly, this regulatory mechanism seems to operate robustly only in microglial but not peripheral microphage cells. Thus, p38 MAPK-ULK1 link is a functional switch that enables microglia to fully engage the inflammatory machinery following the initial stimulation.
 
Reference: J Cell Biol. 2018 Jan 2;217(1):315-328.
 

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