ER-to-Golgi transport machinery promotes the excessive cargo-triggered unfolded protein response in C. elegans
- 1State Key Laboratory of Metabolism and Regulation in Complex Organization, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan, China
- 2Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
- 3University of Chinese Academy of Sciences, Beijing, China
Abstract
Disruption of endoplasmic reticulum (ER) homeostasis activates the unfolded protein response (UPR) to restore proteostasis. Although defects in the secretory machinery can induce ER stress, whether specific trafficking components actively couple cargo handling to UPR signaling remains unclear. Here, using Caenorhabditis elegans genetics, imaging, and biochemical assays, we show that neuronal overexpression of the gap junction protein UNC-9 cell-autonomously activates the IRE-1-XBP-1 branch of the ER UPR. Loss of the early secretory pathway proteins ERGI-2 or ERGI-3 suppresses this response and disrupts UNC-9 localization, revealing functions for these proteins that extend beyond cargo trafficking. ERGI-2 and ERGI-3 interact with both UNC-9 and the ER chaperone HSP-4/BiP, suggesting that they couple the handling of excessive UNC-9 to UPR activation. This requirement is cargo-selective: ERGI-2 and ERGI-3 are dispensable for UPR activation induced by overexpression of another innexin, UNC-7, or unrelated proteins. Moreover, activation of the IRE-1-XBP-1 pathway reduces abnormal UNC-9 accumulation in ergi-2 and ergi-3 mutants. Together, our findings identify ER-to-Golgi trafficking proteins as cargo-selective regulators that link secretory-pathway demand to adaptive UPR. Author summary: Cells must carefully balance protein production, transport, and quality control. When proteins accumulate in the endoplasmic reticulum, cells activate a protective response that helps restore normal function. Although protein transport and stress signaling are closely connected, we still do not fully understand how the machinery that moves proteins through the cell influences this protective response. We used the nematode Caenorhabditis elegans to investigate what happens when neurons produce excessive amounts of UNC-9, a protein used to build communication channels between neighboring cells. We found that excess UNC-9 activates a protective stress response within the neurons producing it. Two proteins involved in transporting newly made proteins from the endoplasmic reticulum, ERGI-2 and ERGI-3, were required for both the normal distribution of UNC-9 and activation of this response. Their involvement was selective: they were not required for stress responses caused by excessive production of several other proteins. We also found that activating the protective response reduced abnormal UNC-9 accumulation. Our findings show that protein-transport machinery can help cells recognize and respond to the burden created by particular proteins. This connection may be especially important in long-lived cells such as neurons, which must maintain protein balance throughout life.
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BibTeX
@article{guan2026ertogolgi,
title = {{ER-to-Golgi transport machinery promotes the excessive cargo-triggered unfolded protein response in C. elegans}},
author = {Liying Guan and Tong Zhang and Zhigao Zhan and Yingchun Wang and Xun Huang and Mei Ding},
journal = {PLOS Genetics},
year = {2026},
month = sep,
doi = {10.1371/journal.pgen.1012301},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012301},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - ER-to-Golgi transport machinery promotes the excessive cargo-triggered unfolded protein response in C. elegans
AU - Liying Guan
AU - Tong Zhang
AU - Zhigao Zhan
AU - Yingchun Wang
AU - Xun Huang
AU - Mei Ding
PY - 2026
DA - 2026/09/08
JO - PLOS Genetics
DO - 10.1371/journal.pgen.1012301
UR - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012301
AB - Disruption of endoplasmic reticulum (ER) homeostasis activates the unfolded protein response (UPR) to restore proteostasis. Although defects in the secretory machinery can induce ER stress, whether specific trafficking components actively couple cargo handling to UPR signaling remains unclear. Here, using Caenorhabditis elegans genetics, imaging, and biochemical assays, we show that neuronal overexpression of the gap junction protein UNC-9 cell-autonomously activates the IRE-1-XBP-1 branch of the ER UPR. Loss of the early secretory pathway proteins ERGI-2 or ERGI-3 suppresses this response and disrupts UNC-9 localization, revealing functions for these proteins that extend beyond cargo trafficking. ERGI-2 and ERGI-3 interact with both UNC-9 and the ER chaperone HSP-4/BiP, suggesting that they couple the handling of excessive UNC-9 to UPR activation. This requirement is cargo-selective: ERGI-2 and ERGI-3 are dispensable for UPR activation induced by overexpression of another innexin, UNC-7, or unrelated proteins. Moreover, activation of the IRE-1-XBP-1 pathway reduces abnormal UNC-9 accumulation in ergi-2 and ergi-3 mutants. Together, our findings identify ER-to-Golgi trafficking proteins as cargo-selective regulators that link secretory-pathway demand to adaptive UPR. Author summary: Cells must carefully balance protein production, transport, and quality control. When proteins accumulate in the endoplasmic reticulum, cells activate a protective response that helps restore normal function. Although protein transport and stress signaling are closely connected, we still do not fully understand how the machinery that moves proteins through the cell influences this protective response. We used the nematode Caenorhabditis elegans to investigate what happens when neurons produce excessive amounts of UNC-9, a protein used to build communication channels between neighboring cells. We found that excess UNC-9 activates a protective stress response within the neurons producing it. Two proteins involved in transporting newly made proteins from the endoplasmic reticulum, ERGI-2 and ERGI-3, were required for both the normal distribution of UNC-9 and activation of this response. Their involvement was selective: they were not required for stress responses caused by excessive production of several other proteins. We also found that activating the protective response reduced abnormal UNC-9 accumulation. Our findings show that protein-transport machinery can help cells recognize and respond to the burden created by particular proteins. This connection may be especially important in long-lived cells such as neurons, which must maintain protein balance throughout life.
SN - 1553-7404
ER -