Autophagy-mediated control of ribosome homeostasis in oncogene-induced senescence

Aida Rodríguez López, Maria H. Jørgensen, Jesper F. Havelund, Frederic S. Arendrup, Srinivasa Prasad Kolapalli, Thorbjørn M. Nielsen, Eva Pais, Carsten Jörn Beese, Ahmad Abdul-Al, Anna Constance Vind, Jiri Bartek, Simon Bekker-Jensen, Marta Montes, Panagiotis Galanos, Nils Faergeman, Lotta Happonen, Lisa B. Frankel*

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Abstract

Oncogene-induced senescence (OIS) is a persistent anti-proliferative response that acts as a barrier against malignant transformation. During OIS, cells undergo dynamic remodeling, which involves alterations in protein and organelle homeostasis through autophagy. Here, we show that ribosomes are selectively targeted for degradation by autophagy during OIS. By characterizing senescence-dependent alterations in the ribosomal interactome, we find that the deubiquitinase USP10 dissociates from the ribosome during the transition to OIS. This release of USP10 leads to an enhanced ribosome ubiquitination, particularly of small subunit proteins, including lysine 275 on RPS2. Both reinforcement of the USP10-ribosome interaction and mutation of RPS2 K275 abrogate ribosomal delivery to lysosomes without affecting bulk autophagy. We show that the selective recruitment of ubiquitinated ribosomes to autophagosomes is mediated by the p62 receptor. While ribophagy is not required for the establishment of senescence per se, it contributes to senescence-related metabolome alterations and facilitates the senescence-associated secretory phenotype.

OriginalsprogEngelsk
Artikelnummer113381
TidsskriftCell Reports
Vol/bind42
Udgave nummer11
Antal sider24
ISSN2211-1247
DOI
StatusUdgivet - 28. nov. 2023

Bibliografisk note

Funding Information:
The global proteome analysis was performed by the Proteomics Research Infrastructure ( PRI ) at the University of Copenhagen (UCPH), supported by the Novo Nordisk Foundation (NNF) ( NNF19SA0059305 ). We acknowledge support from the Swedish National Infrastructure for Biological Mass Spectrometry and the Core Facility for Integrated Microscopy , Faculty of Health and Medical Sciences , University of Copenhagen . The study was additionally supported by the INTEGRA mass spectrometry research infrastructure for proteomics and metabolomics established at SDU by a generous grant from the Novo Nordisk Foundation ( NNF20OC0061575 ). Work in the Frankel lab was supported by the Lundbeck Foundation ( R272-2017-3872 ), the Novo Nordisk Foundation ( NNF19OC0057772 and NNF22OC0079880 ), the Danish Cancer Society ( R269-A15420 and R209-A13011_001 ), and Dansk Kræftforskningsfond ( DKF-2020-75 - (476) ). Work in the Bekker-Jensen lab was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement 863911 - PHYRIST). P.G. was supported by the Lundbeck Foundation ( R322-2019-2577 ).

Funding Information:
The global proteome analysis was performed by the Proteomics Research Infrastructure (PRI) at the University of Copenhagen (UCPH), supported by the Novo Nordisk Foundation (NNF) (NNF19SA0059305). We acknowledge support from the Swedish National Infrastructure for Biological Mass Spectrometry and the Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen. The study was additionally supported by the INTEGRA mass spectrometry research infrastructure for proteomics and metabolomics established at SDU by a generous grant from the Novo Nordisk Foundation (NNF20OC0061575). Work in the Frankel lab was supported by the Lundbeck Foundation (R272-2017-3872), the Novo Nordisk Foundation (NNF19OC0057772 and NNF22OC0079880), the Danish Cancer Society (R269-A15420 and R209-A13011_001), and Dansk Kræftforskningsfond (DKF-2020-75 - (476)). Work in the Bekker-Jensen lab was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement 863911 - PHYRIST). P.G. was supported by the Lundbeck Foundation (R322-2019-2577). L.B.F. and A.R.L. developed the study concept and methodology. A.R.L. M.H.J. A.A.A. T.M.N. C.J.B. S.P.K. P.G. E.P. F.S.F. M.M. and A.C.V. performed experiments, established methodology, and analyzed data. J.H. and N.F. conducted the metabolomics analysis. A.R.L. and L.H. performed and analyzed the LC-MS/MS ribosome interactome data. S.B.-J. J.B. L.H. N.F. and L.B.F. supervised experiments and analysis. L.B.F. and A.R.L. wrote the manuscript. The authors declare no competing interests.

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© 2023 The Authors

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