Inhibition of autophagy promotes ER homeostasis and function in C. elegans

Autophagy is an evolutionarily conserved process for the degradation and recycling of long-lived proteins and organelles in the cell. Misfolded proteins, that are prone to aggregate and cause disease, are among the materials that are cleared by autophagy. Although autophagy controls many aspects of cellular physiology, most autophagy studies have centered on conditions that induce autophagy. Hence, little is known about the consequences of its absence.

Here, using genetic and cell biology approaches in the model organism C. elegans, we demonstrate that autophagy dysfunction can improve ER homeostasis and function. Furthermore, we identified a transcriptional response that underlies the compensatory mechanisms between autophagy dysfunction and improved proteostasis. Taken together, this suggests that autophagy assurance mechanisms are triggered when autophagic flux is disrupted, and activate transcriptional responses that provide alternative solutions that may bypass, at least in part, the need for autophagy.

Since autophagy dysfunction is associated with aging and with several neurodegenerative diseases, this work may open the door toward the development of therapies for treatment of neurological diseases, and diseases associated with defects in protein folding.