title: Autophagy regulates MAVS signaling activation in a phosphorylation-dependent manner in microglia.
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.
authors.affiliation: The State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Cheng
authors.affiliation: The State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|The College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yajin
authors.initials: Y
authors.lastname: Liao
authors.affiliation: The State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xiao
authors.affiliation: The State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|The College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.affiliation: The State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Siqi
authors.initials: S
authors.lastname: Zhao
authors.affiliation: The State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: The Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Baidong
authors.initials: B
authors.lastname: Hou
authors.affiliation: Department of Psychiatry, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, Ontoria K1Z 7K4, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, Ontario K1Z 7K4, Canada.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liang
authors.affiliation: Department of Neurology, Affiliated Drum Tower Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: The State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Zengqiang
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011070:Poly I-C / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008869:Microtubule-Associated Proteins; D011070:Poly I-C; D016315:Proto-Oncogene Proteins c-abl; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C512612:MAVS protein, mouse; C480860:Map1lc3b protein, mouse