{ "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.", "abstract_shown": true, "affiliations": [ "State 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", "Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China", "University of Chinese Academy of Sciences, Beijing, China" ], "article_type": "Research Article", "arxiv": null, "author_total": 6, "authors": [ { "affs": [ 0 ], "name": "Liying Guan" }, { "affs": [ 1 ], "name": "Tong Zhang" }, { "affs": [ 2 ], "name": "Zhigao Zhan" }, { "name": "Yingchun Wang" }, { "name": "Xun Huang" }, { "name": "Mei Ding" } ], "bibtex": "https://research.draconitic.com/paper/0ra81vrqz7ep9.bib", "cited_by": 0, "doi": "10.1371/journal.pgen.1012301", "fulltext_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012301", "id": "0ra81vrqz7ep9", "issns": [ "1553-7404" ], "landing_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012301", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1307|Endoplasmic Reticulum Stress and Disease" ], [ "plos", "/Biology and life sciences/Anatomy/Biological tissue/Muscle tissue/Muscle cells" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Cargo proteins" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Protein transport" ], [ "plos", "/Biology and life sciences/Cell biology/Cell processes/Protein transport" ], [ "plos", "/Biology and life sciences/Cell biology/Cell processes/Secretory pathway/Endoplasmic reticulum" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular structures and organelles/Endoplasmic reticulum" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Muscle cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Neurons" ], [ "plos", "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/Signaling cascades/Stress signaling cascade" ], [ "plos", "/Biology and life sciences/Molecular biology/Molecular biology techniques/Molecular biology assays and analysis techniques/Gene expression and vector techniques/Hyperexpression techniques" ], [ "plos", "/Biology and life sciences/Neuroscience/Cellular neuroscience/Neurons" ], [ "plos", "/Biology and life sciences/Organisms/Eukaryota/Animals/Invertebrates/Nematoda/Caenorhabditis/Caenorhabditis elegans" ], [ "plos", "/Biology and life sciences/Zoology/Animals/Invertebrates/Nematoda/Caenorhabditis/Caenorhabditis elegans" ], [ "plos", "/Medicine and health sciences/Anatomy/Biological tissue/Muscle tissue/Muscle cells" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Animal models/Caenorhabditis elegans" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Model organisms/Caenorhabditis elegans" ], [ "plos", "/Research and analysis methods/Model organisms/Caenorhabditis elegans" ], [ "plos", "/Research and analysis methods/Molecular biology techniques/Molecular biology assays and analysis techniques/Gene expression and vector techniques/Hyperexpression techniques" ] ], "openalex": "W7211963469", "pdf_url": "https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1012301&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-08", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/0ra81vrqz7ep9.ris", "sources": [ { "first_seen": "2026-10-30T12:17:56Z", "native_id": "10.1371/journal.pgen.1012301", "source": "plos", "url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012301" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" } ], "title": "ER-to-Golgi transport machinery promotes the excessive cargo-triggered unfolded protein response in C. elegans", "title_text": "ER-to-Golgi transport machinery promotes the excessive cargo-triggered unfolded protein response in C. elegans", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:56Z", "url": "https://research.draconitic.com/paper/0ra81vrqz7ep9", "venue": "PLOS Genetics", "versions": [] }