The Small Non-coding Vault RNA1-1 Acts as a Riboregulator of Autophagy

• Published in: Cell Vol. 176; no. 5; pp. 1054 - 1067.e12
• Main Authors: Horos, Rastislav, Büscher, Magdalena, Kleinendorst, Rozemarijn, Alleaume, Anne-Marie, Tarafder, Abul K., Schwarzl, Thomas, Dziuba, Dmytro, Tischer, Christian, Zielonka, Elisabeth M., Adak, Asli, Castello, Alfredo, Huber, Wolfgang, Sachse, Carsten, Hentze, Matthias W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.02.2019
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; autophagy; Autophagy - genetics; Cell Line; HeLa Cells; Humans; Mice; non-coding RNA; p62; RAW 264.7 Cells; RNA - metabolism; RNA, Untranslated - metabolism; RNA, Untranslated - physiology; sequestosome-1; Sequestosome-1 Protein - genetics; Sequestosome-1 Protein - metabolism; SQSTM1; starvation; Vault Ribonucleoprotein Particles - genetics; Vault Ribonucleoprotein Particles - metabolism; vault RNA; vtRNA; vtRNA1-1; starvation; vault RNA; autophagy; vtRNA; non-coding RNA; sequestosome-1; vtRNA1-1; p62; SQSTM1
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2019.01.030

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. [Display omitted] •The selective human autophagy receptor p62/sequestosome-1 is an RNA-binding protein•p62 engages the small non-coding vault RNA1-1 as a major interacting RNA•Vault RNA1-1 riboregulates p62-dependent autophagy and aggregate clearance•Mechanistically, vault RNA1-1 interferes with p62 multimerization A biological function of vault RNAs is to directly modulate the oligomerization state of p62, thereby controlling autophagy.