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

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

Loss of USP10 from the ribosome interactome triggers autophagy-mediated degradation of ribosomes during oncogene-induced senescence - Reverse phase pos part

Oncogene-induced senescence (OIS) is a persistent anti-proliferative response regarded as a fail-safe mechanism, which protects against malignant transformation. Yet OIS has pro-tumorigenic effects through the secretion of a diverse group of inflammatory factors, commonly referred to as the senescence-associated secretory phenotype (SASP). During OIS, cells undergo dynamic remodeling, which involves alterations in protein and organelle homeostasis through autophagy. The interplay between autophagy and senescence is complex, and recent evidence suggests a role for selective substrate degradation by autophagy in coordinating the senescent state.Here we show that ribosomes, the complex macromolecular machines central for genetic interpretation in all cells, are selectively targeted for degradation by autophagy during OIS. Using a model system of BRAF-induced OIS in human primary fibroblasts, we find that both small- and large ribosomal subunits are efficiently recruited to autophagosomes and subsequently degraded in lysosomes during OIS. To gain insight into the molecular control of this process, we characterized the ribosome interactomes of proliferative and senescent human fibroblasts. Among the identified senescence-dependent alterations in the ribosome interactome, we found the de-ubiquitinase USP10. While USP10 is present at the ribosome in proliferating cells, its loss from the ribosome upon entry to OIS leads to an enhanced ribosome ubiquitination, particularly of small subunit proteins. Among these are mono-ubiquitination of Lysine 275 on RPS2, which is sufficient to signal for selective uptake of both small and large subunits by the autophagy-lysosomal system during OIS. This occurs, at least in part, via the autophagy cargo receptor protein p62. Both re-enforcement of the USP10-ribosome interaction or mutation of RPS2 K275 could selectively abrogate ribosomal delivery to lysosomes, without impacting bulk autophagy. We show that while ribophagic flux is not required for the establishment of senescence per se, it contributes to senescence-associated metabolome reprogramming and facilitates the SASP response.See 10.6084/m9.figshare.24203823 for reverse phase neg dataSee 10.6084/m9.figshare.24203847 for HILIC neg data</p