TFEB Coordinates Autophagosome Biogenesis and Ribophagy during starvation via SQSTM1

(Macro)autophagy is a cellular degradation pathway that delivers substrates to lysosomes via autophag(Macro)autophagy is a cellular degradation pathway that delivers substrates to lysosomes via autophagosomes. Among physiological stimuli, nutrient starvation is the most potent inducer of autophagy. However, the logic behind the selection of the autophagy substrates during starvation is unclear. During starvation, the transcription factor EB (TFEB) becomes activated and promotes the expression of numerous autophagy-related genes. In this study, we demonstrate that TFEB enhances autophagosome biogenesis by driving the formation of p62/SQSTM1 bodies. Within these structures, we identified ubiquitinated ribosomal proteins as key substrates. We found that the E3 ubiquitin ligase ZNF598, a newly identified TFEB target gene, is upregulated during starvation and promotes the ubiquitination of ribosomal proteins, facilitating their sequestration into SQSTM1 bodies. These findings reveal a transcriptionally coordinated mechanism through which TFEB regulates both ubiquitination and autophagy receptors to direct selective cargo clearance during starvation-induced autophagy.osomes. Among physiological stimuli, nutrient starvation is the most potent inducer of autophagy. However, the logic behind the selection of the autophagy substrates during starvation is unclear. During starvation, the transcription factor EB (TFEB) becomes activated and promotes the expression of numerous autophagy-related genes. In this study, we demonstrate that TFEB enhances autophagosome biogenesis by driving the formation of p62/SQSTM1 bodies. Within these structures, we identified ubiquitinated ribosomal proteins as key substrates. We found that the E3 ubiquitin ligase ZNF598, a newly identified TFEB target gene, is upregulated during starvation and promotes the ubiquitination of ribosomal proteins, facilitating their sequestration into SQSTM1 bodies. These findings reveal a transcriptionally coordinated mechanism through which TFEB regulates both ubiquitination and autophagy receptors to direct selective cargo clearance during starvation-induced autophagy.