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Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing

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, where...

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Main Authors: Thrun, Anna (Author) , Garzia, Aitor (Author) , Kigoshi-Tansho, Yu (Author) , Patil, Pratik Rajendra (Author) , Umbaugh, Charles Samuel (Author) , Dallinger, Teresa (Author) , Liu, Jia (Author) , Kreger, Sylvia (Author) , Patrizi, Annarita (Author) , Cox, Gregory A. (Author) , Tuschl, Thomas (Author) , Joazeiro, Claudio A. P. (Author)
Format: Article (Journal)
Language:English
Published: April 27, 2021
In: Molecular cell
Year: 2021, Volume: 81, Issue: 10, Pages: 2112-2122.e7
ISSN:1097-4164
DOI:10.1016/j.molcel.2021.03.004
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.molcel.2021.03.004
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1097276521001726
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Author Notes:Anna Thrun, Aitor Garzia, Yu Kigoshi-Tansho, Pratik R. Patil, Charles S. Umbaugh, Teresa Dallinger, Jia Liu, Sylvia Kreger, Annarita Patrizi, Gregory A. Cox, Thomas Tuschl, and Claudio A.P. Joazeiro
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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.
Item Description:Gesehen am 14.09.2022
Physical Description:Online Resource
ISSN:1097-4164
DOI:10.1016/j.molcel.2021.03.004

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