Affiliation:
1. Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences Peking University Health Science Center Beijing China
2. Institute of Precision Medicine Peking University Shenzhen Hospital Shenzhen China
Abstract
AbstractStress granules are dynamic cytoplasmic ribonucleoprotein granules that assemble in response to cellular stress. Aberrant formation of stress granules has been linked to neurodegenerative diseases. However, the molecular mechanisms underlying the initiation of stress granules remain elusive. Here we report that the brain‐enriched protein kinase FAM69C promotes stress granule assembly through phosphorylation of eukaryotic translation initiation factor 2 (eIF2α). FAM69C physically interacts with eIF2α and functions as a stress‐specific kinase for eIF2α, leading to stress‐induced protein translation arrest and stress granule assembly. Primary microglia derived from Fam69c knockout mice exhibit aberrant stress granule assembly in response to oxidative stress and ATP. Defective stress granule assembly in microglia correlates with the formation of ASC specks and NLRP3 inflammasome activation, whereas induction of stress granule precludes inflammasome formation. Consistently, increased NLRP3 levels, caspase‐1 cleavage and Il18 expression corroborate microglia‐associated neuroinflammation in aged Fam69c knockout mice. Our study demonstrates that FAM69C is critical for stress granule assembly and suggests its role in the regulation of microglia function.
Funder
National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
Genetics,Molecular Biology,Biochemistry
Cited by
9 articles.
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