Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing
| Autor: | Anna Thrun, Annarita Patrizi, Charles S. Umbaugh, Teresa Dallinger, Sylvia Kreger, Pratik R. Patil, Claudio A. P. Joazeiro, Jia Liu, Gregory A. Cox, Yu Kigoshi-Tansho, Aitor Garzia, Thomas Tuschl |
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| Rok vydání: | 2021 |
| Předmět: |
Nucleocytoplasmic Transport Proteins
Proteasome Endopeptidase Complex Proteases Ubiquitin-Protein Ligases Proteolysis medicine.disease_cause Models Biological Ribosome Article 03 medical and health sciences 0302 clinical medicine Ubiquitin Antigens Neoplasm medicine Animals Humans Receptors Cytokine Nuclear export signal Molecular Biology 030304 developmental biology Mammals Alanine 0303 health sciences Mutation biology medicine.diagnostic_test Ubiquitination Cell Biology Salivary Proline-Rich Proteins Ubiquitin ligase Cell biology biology.protein Ribosomes 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Mol Cell |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2021.03.004 |
| Popis: | Summary 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 CRL2KLHDC10 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. |
| Databáze: | OpenAIRE |
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