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
Affiliations
Aida Rodríguez López
Danish Cancer Institute, 2100 Copenhagen, Denmark
Maria H. Jørgensen
Danish Cancer Institute, 2100 Copenhagen, Denmark
Jesper F. Havelund
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark
Frederic S. Arendrup
Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark
Srinivasa Prasad Kolapalli
Danish Cancer Institute, 2100 Copenhagen, Denmark
Thorbjørn M. Nielsen
Danish Cancer Institute, 2100 Copenhagen, Denmark
Eva Pais
Danish Cancer Institute, 2100 Copenhagen, Denmark
Carsten Jörn Beese
Danish Cancer Institute, 2100 Copenhagen, Denmark
Ahmad Abdul-Al
Danish Cancer Institute, 2100 Copenhagen, Denmark
Anna Constance Vind
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark
Jiri Bartek
Danish Cancer Institute, 2100 Copenhagen, Denmark; Department of Medical Biochemistry and Biophysics, Division of Genome Biology, Science for Life Laboratory, Karolinska Institute, 171 21 Stockholm, Sweden
Simon Bekker-Jensen
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark
Marta Montes
Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark
Panagiotis Galanos
Danish Cancer Institute, 2100 Copenhagen, Denmark
Nils Faergeman
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark
Lotta Happonen
Division of Infection Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, 221 84 Lund, Sweden
Lisa B. Frankel
Danish Cancer Institute, 2100 Copenhagen, Denmark; Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark; Corresponding author
Summary: 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.