Department of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02453, USA.
Department of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02453, USA.
Cell Rep. 2023 Oct 31;42(10):113283. doi: 10.1016/j.celrep.2023.113283. Epub 2023 Oct 19.
Cells activate stress response pathways to survive adverse conditions. Such responses involve the inhibition of global cap-dependent translation. This inhibition is a block that essential transcripts must escape via alternative methods of translation initiation, e.g., an internal ribosome entry site (IRES). IRESs have distinct structures and generally require a limited repertoire of translation factors. Cellular IRESs have been identified in many critical cellular stress response transcripts. We previously identified cellular IRESs in the murine insulin receptor (Insr) and insulin-like growth factor 1 receptor (Igf1r) transcripts and demonstrated their resistance to eukaryotic initiation factor 4F (eIF4F) inhibition. Here, we find that eIF5B preferentially promotes Insr, Igf1r, and hepatitis C virus IRES activity through a non-canonical mechanism that requires its highly charged and disordered N terminus. We find that the N-terminal region of eIF5B can drive cytoplasmic granule formation. This eIF5B granule is triggered by cellular stress and is sufficient to specifically promote IRES activity.
细胞激活应激反应途径以在不利条件下存活。这种反应涉及到抑制全球帽依赖性翻译。这种抑制是一种阻断，必要的转录本必须通过翻译起始的替代方法逃脱，例如内部核糖体进入位点 (IRES)。IRES 具有不同的结构，通常需要有限的翻译因子库。已经在许多关键的细胞应激反应转录本中鉴定出细胞 IRES。我们之前在小鼠胰岛素受体 (Insr) 和胰岛素样生长因子 1 受体 (Igf1r) 转录本中鉴定出细胞 IRES，并证明它们对真核起始因子 4F (eIF4F) 抑制的抗性。在这里，我们发现 eIF5B 通过一种非典型机制优先促进 Insr、Igf1r 和丙型肝炎病毒 IRES 活性，该机制需要其带高电荷和无序的 N 端。我们发现 eIF5B 的 N 端区域可以驱动细胞质颗粒的形成。这种 eIF5B 颗粒由细胞应激触发，足以特异性地促进 IRES 活性。
