Autophagy regulates MAVS signaling activation in a phosphorylation-dependent manner in microglia

Jinbo Cheng; Yajin Liao; Lei Xiao; Rong Wu; Siqi Zhao; Hong Chen; Baidong Hou; Xia Zhang; Chengyu Liang; Yun Xu; Zengqiang Yuan

doi:10.1038/cdd.2016.121

Autophagy regulates MAVS signaling activation in a phosphorylation-dependent manner in microglia

Cell Death Differ. 2017 Feb;24(2):276-287. doi: 10.1038/cdd.2016.121. Epub 2016 Nov 4.

Authors

Jinbo Cheng¹, Yajin Liao^{1

2}, Lei Xiao¹, Rong Wu^{1

2}, Siqi Zhao^{1

3}, Hong Chen¹, Baidong Hou⁴, Xia Zhang^{5

6}, Chengyu Liang⁷, Yun Xu⁸, Zengqiang Yuan^{1

3}

Affiliations

¹ The State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
² The College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
³ Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China.
⁴ The Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁵ Department of Psychiatry, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, Ontoria K1Z 7K4, Canada.
⁶ Department of Cellular and Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, Ontario K1Z 7K4, Canada.
⁷ Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
⁸ Department of Neurology, Affiliated Drum Tower Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu, China.

Abstract

Mitochondrial antiviral signaling (MAVS) protein has an important role in antiviral immunity and autoimmunity. However, the pathophysiological role of this signaling pathway, especially in the brain, remains elusive. Here we demonstrated that MAVS signaling existed and mediated poly(I:C)-induced inflammation in the brain. Along with the MAVS signaling activation, there was an induction of autophagic activation. Autophagy negatively regulated the activity of MAVS through direct binding of LC3 to the LIR motif Y(9)xxI(12) of MAVS. We also found that c-Abl kinase phosphorylated MAVS and regulated its interaction with LC3. Interestingly, tyrosine phosphorylation of MAVS was required for downstream signaling activation. Importantly, in vivo data showed that the deficiency of MAVS or c-Abl prevented MPTP-induced microglial activation and dopaminergic neuron loss. Together, our findings reveal the molecular mechanisms underlying the regulation of MAVS-dependent microglial activation in the nervous system, thus providing a potential target for the treatment of microglia-driven inflammatory brain diseases.

MeSH terms

Adaptor Proteins, Signal Transducing / deficiency
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Autophagy* / drug effects
Cells, Cultured
Dopaminergic Neurons / drug effects
Dopaminergic Neurons / metabolism
HEK293 Cells
Humans
Inflammation / chemically induced
MPTP Poisoning
Male
Mice
Mice, Knockout
Microglia / cytology
Microglia / drug effects
Microglia / metabolism
Microtubule-Associated Proteins / antagonists & inhibitors
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism
Phosphorylation / drug effects
Poly I-C / pharmacology
Proto-Oncogene Proteins c-abl / metabolism
RNA Interference
Reactive Oxygen Species / metabolism
Signal Transduction* / drug effects
Tumor Necrosis Factor-alpha / analysis
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / metabolism

Substances

Adaptor Proteins, Signal Transducing
IPS-1 protein, mouse
Map1lc3b protein, mouse
Microtubule-Associated Proteins
Reactive Oxygen Species
Tumor Necrosis Factor-alpha
Proto-Oncogene Proteins c-abl
Poly I-C

Grants and funding

R01 CA140964/CA/NCI NIH HHS/United States