Ribosome biogenesis restricts innate immune responses to virus infection and DNA
Ribosome biogenesis restricts innate immune responses to virus infection and DNA
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DOI：
10.7554/elife.49551
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发表时间：
2019-12-16
期刊：
影响因子：
7.7
通讯作者：
Mohr, Ian
中科院分区：
文献类型：
--
作者：
Bianco, Christopher;Mohr, Ian
核糖体在生物学中具有普遍的重要性，其生产受到发育障碍、癌症和病毒感染的失调。虽然推测蛋白质合成是必需的，但核糖体生物发生如何影响病毒复制和细胞固有免疫反应仍未得到测试。令人惊讶的是，我们发现限制核糖体的生物发生刺激了人巨细胞病毒(HCMV)的复制，而不抑制翻译。干扰核糖体RNA(RRNA)的积累引发了核仁压力并抑制了1392个基因的表达，其中包括高迁移率族蛋白2(HMGB2)，这是一种染色质相关蛋白，有助于cGAS对细胞质双链DNA的感知。此外，它还降低了细胞质中HMGB2的丰度，并削弱了对未感染细胞中对HCMV或dsDNA的反应的干扰素β(IFNB1)mRNA的诱导，而干扰素β是一种关键的抗增殖、促炎症细胞因子。这证实了rRNA的积累通过控制HMGB2的丰度来调节对dsDNA的先天免疫反应。此外，它揭示了rRNA的积累和/或核仁的活动出人意料地调节dsDNA的传感，从而限制病毒的复制和调节炎症。
Ribosomes are universally important in biology and their production is dysregulated by developmental disorders, cancer, and virus infection. Although presumed required for protein synthesis, how ribosome biogenesis impacts virus reproduction and cell-intrinsic immune responses remains untested. Surprisingly, we find that restricting ribosome biogenesis stimulated human cytomegalovirus (HCMV) replication without suppressing translation. Interfering with ribosomal RNA (rRNA) accumulation triggered nucleolar stress and repressed expression of 1392 genes, including High Mobility Group Box 2 (HMGB2), a chromatin-associated protein that facilitates cytoplasmic double-stranded (ds) DNA-sensing by cGAS. Furthermore, it reduced cytoplasmic HMGB2 abundance and impaired induction of interferon beta (IFNB1) mRNA, which encodes a critical anti-proliferative, proinflammatory cytokine, in response to HCMV or dsDNA in uninfected cells. This establishes that rRNA accumulation regulates innate immune responses to dsDNA by controlling HMGB2 abundance. Moreover, it reveals that rRNA accumulation and/or nucleolar activity unexpectedly regulate dsDNA-sensing to restrict virus reproduction and regulate inflammation.