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Phosphatidylcholine coordinates ER-autonomous and ER-nonautonomous adaptations to unfolded protein response
Haixiang Tong1, Wei Li1, Pangui Yuan1
1School of Life Sciences, Chongqing University, Chongqing, China.
The Journal of Biological Chemistry
|December 8, 2025
Summary
Cellular stress responses adapt to endoplasmic reticulum unfolded protein response (UPR) defects by activating both ER-autonomous and ER-nonautonomous pathways. Phosphatidylcholine metabolism links ER UPR function to lysosomal activity, promoting longevity.
Area of Science:
- Cellular Biology
- Molecular Biology
- Aging Research
Background:
- The endoplasmic reticulum unfolded protein response (ER UPR) is vital for maintaining proteostasis.
- ER UPR dysfunction is linked to aging and various diseases.
- Cellular mechanisms for coping with ER UPR dysfunction are not fully understood.
Purpose of the Study:
- To investigate adaptive responses to defects in the IRE1/XBP1 UPR branch.
- To elucidate the role of phosphatidylcholine (PC) metabolism in proteostasis.
- To understand how cells maintain proteostasis under compromised ER UPR conditions.
Main Methods:
- Utilized Caenorhabditis elegans as a model organism.
- Investigated the IRE1/XBP1 and PEK1 UPR branches.
- Analyzed phosphatidylcholine metabolism and lysosomal function.
Main Results:
- IRE1/XBP1 dysfunction activated the PEK1 UPR branch and a lysosome-dependent cytosolic proteostatic response.
- IRE1/XBP1 dysfunction led to reduced phosphatidylcholine levels, triggering lysosomal activation.
- Suppression of phosphatidylcholine metabolism alone activated ER UPR and lysosomal pathways, enhancing stress resilience and longevity.
Conclusions:
- Cells employ integrated ER-autonomous and ER-nonautonomous responses to maintain proteostasis during ER UPR dysfunction.
- Phosphatidylcholine metabolism is a key regulator linking ER UPR, lysosomal activity, and systemic proteostasis.
- Targeting phosphatidylcholine metabolism may offer strategies for enhancing resilience to proteostatic stress and promoting healthy aging.
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