FAM69C promotes stress granule assembly and suppresses inflammasome activation

Stress granule and inflammasome assembly determine contrasting fates of stressed cells. FAM69C is a brain-enriched kinase associated with neurodegenerative diseases, but its biological functions are still largely unknown. Here we show that FAM69C plays an important role in the regulation of stress responses through promoting stress granule assembly and suppressing inflammasome activation. In response to ATP, a common inflammasome activator, mouse primary microglia, and BV-2 cells form stress granules. FAM69C deficiency hastens inflammasome activation in mouse microglia, which is accompanied by inhibited stress granule assembly. FAM69C promotes the assembly of stress granules and halts protein translation under stress. Aged Fam69c knockout mice show increased neuroinflammation and ASC specks formation. We further find that FAM69C physically phosphorylates eIF2alpha and promotes stress granule assembly. Our data reveal that FAM69C promotes stress granule assembly under stress and suppresses inflammasome formation in microglia, suggesting that FAM69C may be a potential therapeutic target for neurodegenerative diseases. Cerebral cortex mRNA profiles of 12-month-old wild type (WT) and Fam69c-/- mice were generated by deep sequencing, in triplicate, using Illumina NovaSeq 6000.应激颗粒（stress granule）与炎性小体（inflammasome）的组装决定了应激细胞的迥异命运。FAM69C是一种脑富集激酶，与神经退行性疾病密切相关，但其生物学功能目前仍未得到充分阐释。本研究证实，FAM69C可通过促进应激颗粒组装并抑制炎性小体活化，在应激反应调控中发挥关键作用。作为常见的炎性小体活化剂，三磷酸腺苷（ATP）可诱导小鼠原代小胶质细胞与BV-2细胞形成应激颗粒。FAM69C缺陷会加速小鼠小胶质细胞的炎性小体活化，同时伴随应激颗粒组装的受抑。在应激状态下，FAM69C可促进应激颗粒组装并阻断蛋白质翻译进程。老龄Fam69c基因敲除小鼠表现出更为显著的神经炎症与ASC斑点形成。本研究进一步发现，FAM69C可直接磷酸化真核翻译起始因子2α（eIF2α），并以此介导应激颗粒组装。本研究数据表明，FAM69C可在应激状态下促进小胶质细胞的应激颗粒组装，并抑制炎性小体形成，提示FAM69C或可作为神经退行性疾病的潜在治疗靶点。本研究采用Illumina NovaSeq 6000测序平台，对12月龄野生型（WT）与Fam69c基因敲除（Fam69c-/-）小鼠的大脑皮层mRNA表达谱进行了三次生物学重复的深度测序。