European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Cell. 2019 Feb 21;176(5):1054-1067.e12. doi: 10.1016/j.cell.2019.01.030. Epub 2019 Feb 14.
Vault RNAs (vtRNA) are small non-coding RNAs transcribed by RNA polymerase III found in many eukaryotes. Although they have been linked to drug resistance, apoptosis, and viral replication, their molecular functions remain unclear. Here, we show that vault RNAs directly bind the autophagy receptor sequestosome-1/p62 in human and murine cells. Overexpression of human vtRNA1-1 inhibits, while its antisense LNA-mediated knockdown enhances p62-dependent autophagy. Starvation of cells reduces the steady-state and p62-bound levels of vault RNA1-1 and induces autophagy. Mechanistically, p62 mutants that fail to bind vtRNAs display increased p62 homo-oligomerization and augmented interaction with autophagic effectors. Thus, vtRNA1-1 directly regulates selective autophagy by binding p62 and interference with oligomerization, a critical step of p62 function. Our data uncover a striking example of the potential of RNA to control protein functions directly, as previously recognized for protein-protein interactions and post-translational modifications.
穹窿 RNA（vtRNA）是由 RNA 聚合酶 III 转录的小型非编码 RNA，存在于许多真核生物中。尽管它们与耐药性、细胞凋亡和病毒复制有关，但它们的分子功能仍不清楚。在这里，我们表明 vault RNAs 可直接与人源和鼠源细胞中的自噬受体 sequestosome-1/p62 结合。人源 vtRNA1-1 的过表达会抑制其作用，而其反义锁核酸介导的敲低则增强了 p62 依赖性自噬。细胞饥饿会降低 vault RNA1-1 的稳态和与 p62 结合的水平，并诱导自噬。从机制上讲，无法与 vtRNAs 结合的 p62 突变体显示出 p62 同源寡聚化增加，并增强与自噬效应物的相互作用。因此，vtRNA1-1 通过与 p62 结合并干扰寡聚化直接调节选择性自噬，这是 p62 功能的关键步骤。我们的数据揭示了一个引人注目的例子，说明 RNA 可以直接控制蛋白质功能，就像以前认识到的那样，蛋白质-蛋白质相互作用和翻译后修饰也可以控制蛋白质功能。
