FAM69C functions as a kinase for eIF2α and promotes stress granule assembly

• Published in: EMBO reports 2023-05, Vol.24 (5), p.e55641-n/a
• Main Authors: Wu, Zhongyan, Mei, Fan, Gan, Yangyang, Liu, Anhang, Hu, Jiapan, Jin, Yan, Yin, Yuxin
• Format: Article
• Language: English
• Subjects: Animals; Caspase; Cytoplasmic Granules - metabolism; eIF2α; EMBO19; EMBO27; EMBO37; Eukaryotic Initiation Factor-2 - genetics; Eukaryotic Initiation Factor-2 - metabolism; FAM69C; Granular materials; inflammasome; Inflammasomes; Inflammasomes - metabolism; Inflammation; Initiation factor eIF-2; Interleukin 18; Kinases; Life Sciences; Mice; Mice, Knockout; Microglia; Molecular modelling; Neurodegenerative diseases; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Oxidative stress; Phosphorylation; stress granule; Stress Granules
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202255641

Stress 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. Synopsis FAM69C is a novel stress‐specific kinase for eIF2α and promotes stress granule assembly, which precludes NLRP3 inflammasome activation in microglia. FAM69C functions as a stress‐specific kinase for eIF2α and promotes stress granule assembly. Defective stress granule assembly in Fam69c −/− microglia correlates with inflammasome activation. Graphical Abstract FAM69C is a novel stress‐specific kinase for eIF2α and promotes stress granule assembly, which precludes NLRP3 inflammasome activation in microglia.