Estrogen-related receptor alpha regulates ribosomal translation to sustain chronic lysosomal function during starvation

Starvation is a physiological stress to the cell during resource limiting conditions. Under such conditions, general transcription and translation may be resource consuming and futile. Cells have to converge their resources towards their survival by maximizing macromolecular recycling by lysosomal degradative pathways such as autophagy during chronic starvation. We have identified that there was a temporal decline in protein translation during early starvation in vivo and in vitro, which later increased to sustain lysosome-autophagy function during chronic starvation. Interestingly, proteomics analysis during chronic starvation revealed that proteins regulating ribosome and lysosome functions are enriched along with significant upregulation of Ppargc1a-Esrra axis. Furthermore, starvation-induced Esrra is positively associated with increased lysosomal proteins and autophagy. Pharmacological inhibition of Esrra inhibited ribosome and lysosomal proteins and function under starvation. Thus, we found that Esrra is indispensable for translation of lysosomal proteins and function during chronic starvation that is required for cell survival.