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

Area of Science:

• Cellular Biology
• Molecular Oncology
• Autophagy Research

Background:

• Oncogene-induced senescence (OIS) is a crucial anti-cancer mechanism involving cellular remodeling and altered homeostasis.
• Autophagy plays a role in maintaining cellular balance during OIS, but its specific targets remain incompletely understood.

Purpose of the Study:

• To investigate the selective degradation of ribosomes by autophagy during OIS.
• To elucidate the molecular mechanisms governing ribophagy in senescent cells.
• To determine the functional consequences of ribophagy in OIS.

Main Methods:

• Characterization of senescence-dependent alterations in the ribosomal interactome.
• Analysis of the deubiquitinase USP10's interaction with ribosomes during OIS.
• Investigation of RPS2 ubiquitination and its role in ribosome degradation.
• Assessment of p62-mediated recruitment of ubiquitinated ribosomes to autophagosomes.
• Evaluation of the impact of ribophagy on senescence establishment, metabolome, and secretory phenotype.

Main Results:

• Ribosomes are selectively degraded by autophagy during OIS (ribophagy).
• USP10 dissociates from ribosomes during OIS, leading to increased ribosome ubiquitination.
• Ubiquitinated ribosomes, specifically RPS2 K275, are targeted for lysosomal degradation via p62.
• Ribophagy is not essential for senescence establishment but influences senescence-related metabolic changes and the secretory phenotype.

Conclusions:

• Selective autophagic degradation of ribosomes (ribophagy) is a novel component of the OIS response.
• The USP10-ribosome-p62 axis mediates ribophagy during OIS.
• Ribophagy contributes to the functional outcomes of OIS, including metabolic reprogramming and the senescence-associated secretory phenotype.