# Phosphatidylcholine coordinates ER-autonomous and ER-nonautonomous adaptations to unfolded protein response dysfunction

## TL;DR

This study shows how cells adapt to stress in the endoplasmic reticulum by regulating a key lipid called phosphatidylcholine, which helps maintain protein balance and even extends lifespan.

## Contribution

The study identifies phosphatidylcholine as a novel regulator of proteostasis and aging through its role in coordinating ER and lysosomal responses.

## Key findings

- IRE-1/XBP-1 dysfunction activates both ER and lysosomal proteostatic responses.
- Phosphatidylcholine deficiency triggers lysosomal activation via the BORC complex.
- Reducing phosphatidylcholine metabolism alone enhances resilience to stress and longevity.

## Abstract

The ER UPR plays a crucial role in maintaining proteostasis, with its dysfunction closely associated with aging and various diseases. However, how cells cope with ER UPR dysfunction remains largely unexplored. Here, we report that both ER-autonomous and ER-nonautonomous adaptive responses are activated by defects in the IRE-1/XBP-1 UPR branch in Caenorhabditis elegans. IRE-1/XBP-1 dysfunction not only triggers the activation of the PEK-1 UPR branch but also induces a lysosome-dependent cytosolic proteostatic response. Mechanistically, IRE-1/XBP-1 dysfunction downregulates phosphatidylcholine (PC) metabolism, reducing levels of membrane lipid PC. This PC deficiency drives BORC complex recruitment to lysosomes, triggering lysosomal activation. Furthermore, suppression of phosphatidylcholine metabolism alone sufficiently activates both the ER UPR and lysosomal pathways, thereby enhancing resilience to proteostatic stress and contributing to longevity. These findings provide insights into how cells integrate distinct adaptive responses to maintain systemic proteostasis when the ER UPR is compromised and identify phosphatidylcholine as a potent regulator of proteostasis and aging.