Abstract
Cold affects many aspects of biology, medicine, agriculture, and industry. Here, we identify a conserved endoplasmic reticulum (ER) stress response, distinct from the canonical unfolded protein response, that maintains lipid homeostasis during extreme cold. We establish that the ER stress sensor IRE-1 is critical for resistance to extreme cold and activated by cold temperature. Specifically, neuronal IRE-1 signals through JNK-1 and neuropeptide signaling to regulate lipid composition within the animal. This cold-response pathway can be bypassed by dietary supplementation with unsaturated fatty acids. Altogether, our findings define an ER-centric conserved organism-wide cold stress response, consisting of molecular neuronal sensors, effectors, and signaling moieties, which control adaptation to cold conditions in the organism. Better understanding of the molecular basis of this stress response is crucial for the optimal use of cold conditions on live organisms and manipulation of lipid saturation homeostasis, which is perturbed in human pathologies.
| Original language | English |
|---|---|
| Article number | 111739 |
| Journal | Cell Reports |
| Volume | 41 |
| Issue number | 9 |
| DOIs | |
| State | Published - 29 Nov 2022 |
Bibliographical note
Funding Information:We thank members of the Henis-Korenblit laboratory for helpful discussions. Some nematode strains were provided by the Caenorhabditis Genetics Center, Minnesota, funded by the National Institutes of Health Office of Research Infrastructure Programs ( P40 OD010440 ), and Dr. Shohei Mitani (National Bioresource Project for the nematode, Tokyo Women’s Medical University School of Medicine, Japan). We thank Dr. Kang Shen (Stanford University, USA) for IRE-1 structure functional strains (wy782, wy762), Dr. Rebecca Taylor (University of Cambridge, United Kingdom) for xbp-1s expression strains, and Dr. Keith Blackwell (Harvard University, USA) for the IRE-1(C663S) transgenic strain. This work was supported by funds from the Israel Science Foundation (ISF grant no. 689/19 to S.H.K.), the traveling fellowship from The Company of Biologists ( JCSTF18118 to R.D.), the Singapore Ministry of Education Academic Research Fund Tier 3 ( MOE-MOET32020-0001 to G.T.), the Ministry of Health, Singapore , National Medical Research Council Open Fund Individual Research Grant ( MOH-000566 to G.T.), and the S Research Scholarship to J.H.K. (predoctoral fellowship).
Funding Information:
We thank members of the Henis-Korenblit laboratory for helpful discussions. Some nematode strains were provided by the Caenorhabditis Genetics Center, Minnesota, funded by the National Institutes of Health Office of Research Infrastructure Programs (P40 OD010440), and Dr. Shohei Mitani (National Bioresource Project for the nematode, Tokyo Women's Medical University School of Medicine, Japan). We thank Dr. Kang Shen (Stanford University, USA) for IRE-1 structure functional strains (wy782, wy762), Dr. Rebecca Taylor (University of Cambridge, United Kingdom) for xbp-1s expression strains, and Dr. Keith Blackwell (Harvard University, USA) for the IRE-1(C663S) transgenic strain. This work was supported by funds from the Israel Science Foundation (ISF grant no. 689/19 to S.H.K.), the traveling fellowship from The Company of Biologists (JCSTF18118 to R.D.), the Singapore Ministry of Education Academic Research Fund Tier 3 (MOE-MOET32020-0001 to G.T.), the Ministry of Health, Singapore, National Medical Research Council Open Fund Individual Research Grant (MOH-000566 to G.T.), and the S Research Scholarship to J.H.K. (predoctoral fellowship). R.D. conceptualization and design of experiments, methodology, data analysis, figure preparation, and manuscript writing; J.H.K. methodology, formal analysis, and investigation; C.B.-C. methodology, formal analysis, and investigation; C.C. software, formal analysis, data curation, visualization, and writing – review & editing; I.L.-L. methodology, formal analysis; S.K.-L. and S.A.-A. methodology; G.T. and S.H.-K. conceptualization, methodology, formal analysis, visualization, supervision, writing – original draft, and writing – review & editing. The authors declare no competing interests.
Publisher Copyright:
© 2022 The Author(s)
Keywords
- C. elegans
- CP: Metabolism
- IRE-1
- IRE1
- JNK
- cell non-autonomous stress response
- cold stress
- endoplasmic reticulum
- fat metabolism
- lipids
- unfolded protein response
