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

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

Author information

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.

PMID:
28141795
PMCID:
PMC5299710
DOI:
10.1038/cdd.2016.121
[Indexed for MEDLINE]
Free PMC Article

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