Mechanisms of Proteostasis that Compensate for Defective Autophagy

Autophagy is an essential cellular mechanism for lysosome-dependent degradation and recycling of molecules and subcellular structures such as proteins, lipids or organelles. Autophagy plays a crucial role in maintaining cellular homeostasis during development as well as aging, whereas disruption of autophagy has been linked to cancer, neurodegeneration and infectious diseases. While autophagy is considered beneficial for overall homeostasis, we demonstrate a compensatory cellular program that maintains proteostasis when macroautophagy flux is impaired, which has not been previously described. We find that autophagy-deficient C. elegans mutants display improved survival when challenged to develop in the presence of ER stress. This compensatory response requires the unfolded protein response (UPR) sensor IRE-1 and the transcription factor DAF-16, as well as the lysosome-biogenesis transcription factor HLH-30/TFEB. Overall, we demonstrate that autophagy impairment promotes ER stress resistance during development due to activation of transcriptional programs and the UPR. Understanding the mechanisms behind this autophagy-compensatory stress response may enable the future development of therapeutics to cure proteostasis-related diseases.