| First Author | Thrun A | Year | 2021 |
| Journal | Mol Cell | Volume | 81 |
| Issue | 10 | Pages | 2112-2122.e7 |
| PubMed ID | 33909987 | Mgi Jnum | J:333974 |
| Mgi Id | MGI:6718911 | Doi | 10.1016/j.molcel.2021.03.004 |
| Citation | Thrun A, et al. (2021) Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing. Mol Cell 81(10):2112-2122.e7 |
| abstractText | Incompletely synthesized nascent chains obstructing large ribosomal subunits are targeted for degradation by ribosome-associated quality control (RQC). In bacterial RQC, RqcH marks the nascent chains with C-terminal alanine (Ala) tails that are directly recognized by proteasome-like proteases, whereas in eukaryotes, RqcH orthologs (Rqc2/NEMF [nuclear export mediator factor]) assist the Ltn1/Listerin E3 ligase in nascent chain ubiquitylation. Here, we study RQC-mediated proteolytic targeting of ribosome stalling products in mammalian cells. We show that mammalian NEMF has an additional, Listerin-independent proteolytic role, which, as in bacteria, is mediated by tRNA-Ala binding and Ala tailing. However, in mammalian cells Ala tails signal proteolysis indirectly, through a pathway that recognizes C-terminal degrons; we identify the CRL2(KLHDC10) E3 ligase complex and the novel C-end rule E3, Pirh2/Rchy1, as bona fide RQC pathway components that directly bind to Ala-tailed ribosome stalling products and target them for degradation. As Listerin mutation causes neurodegeneration in mice, functionally redundant E3s may likewise be implicated in molecular mechanisms of neurodegeneration. |
