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Homeostasis control in health and disease by the unfolded protein response

Nature Reviews Molecular Cell Biology volume 26, pages 193–212 (2025)Cite this article

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Abstract

Cells rely on the endoplasmic reticulum (ER) to fold and assemble newly synthesized transmembrane and secretory proteins — essential for cellular structure–function and for both intracellular and intercellular communication. To ensure the operative fidelity of the ER, eukaryotic cells leverage the unfolded protein response (UPR) — a stress-sensing and signalling network that maintains homeostasis by rebalancing the biosynthetic capacity of the ER according to need. The metazoan UPR can also redirect signalling from cytoprotective adaptation to programmed cell death if homeostasis restoration fails. As such, the UPR benefits multicellular organisms by preserving optimally functioning cells while removing damaged ones. Nevertheless, dysregulation of the UPR can be harmful. In this Review, we discuss the UPR and its regulatory processes as a paradigm in health and disease. We highlight important recent advances in molecular and mechanistic understanding of the UPR that enable greater precision in designing and developing innovative strategies to harness its potential for therapeutic gain. We underscore the rheostatic character of the UPR, its contextual nature and critical open questions for its further elucidation.

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Fig. 1: Dynamic, tunable unfolded protein response signalling and outcomes in health and disease.
Fig. 2: Functional diversification of the unfolded protein response across evolutionary scales.
Fig. 3: Homeostatic regulation by the unfolded protein response across biological levels.
Fig. 4: The unfolded protein response programmes.
Fig. 5: The unfolded protein response in disease.

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Acknowledgements

J.M.H. is supported by the German Cancer Aid.

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  1. These authors contributed equally: Diego Acosta-Alvear, Jonathan M. Harnoss.

Authors and Affiliations

  1. Altos Labs, Inc., Bay Area Institute of Science, Redwood City, CA, USA

    Diego Acosta-Alvear & Peter Walter

  2. Department of General, Visceral, Thoracic and Transplant Surgery, University Hospital Giessen, Giessen, Germany

    Jonathan M. Harnoss

  3. Research Oncology, Genentech, Inc., South San Francisco, CA, USA

    Avi Ashkenazi

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Glossary

ABC transporters

Superfamily of proteins that transport substances across biological membranes.

Antigen cross-presentation

A cellular process in which antigen-presenting cells acquire and process antigenic molecules and present them to effector cells of the immune system.

Arterial intima

Innermost region of the artery, encompassing the endothelium lining the arterial walls at the arterial lumen.

Cis-regulatory elements

Non-coding DNA sequences that regulate transcription of adjacent DNA.

DNA damage–repair response

(DDR). A homeostatic signalling network comprising sensors of genome damage and effectors in charge of genome repair.

ER–mitochondria contact sites

Dynamic multiprotein structures forming physical contacts between the endoplasmic reticulum and mitochondria.

Goblet cells

Specialized epithelial cells that reside in the mucosal layer of the intestinal tract and the airways and secrete mucus.

Heat shock response

A homeostatic signalling network that detects protein-folding deviations in the cytosol and induces gene-expression programmes to augment chaperones to aid in protein refolding and damage clearance.

Hypothalamic pro-opiomelanocortin neurons

Neurons that regulate metabolism and energy expenditure.

Hedgehog ligands and receptors

Interacting proteins governing the Hedgehog signalling pathway: an important developmental control pathway in animals.

Inositol triphosphate receptors

Calcium channels in the endoplasmic reticulum (ER) membrane that release calcium from the ER lumen.

Integrated stress response

A homeostatic signalling network that detects and reacts to different stresses and reprogrammes the transcriptome and proteome to leverage the biosynthetic capacity of the cell with stress levels.

Ischaemia–reperfusion injury

Injury that occurs when blood flow is restored after a period of ischaemia (restriction of blood flow to a tissue).

Kar2 (also known as BiP)

The most abundant Hsp70-type chaperone in the lumen of the endoplasmic reticulum of yeast (Kar2) and animals (BiP).

KRAS

KRAS (and HRAS) are cancer-causing genes, or oncogenes, often activated by mutation in cancer and encoding proteins that transduce growth signals.

Lamin A

Structural protein and a major component of the nuclear lamina: a fibrillar meshwork providing mechanical support to the nucleus of the cell.

Muscle satellite-cell

Skeletal muscle stem cells responsible for tissue growth, repair and regeneration.

Myogenic regulatory factors

A family of transcription factors driving gene expression programmes behind developmental and regenerative muscle differentiation.

Osteoclastogenesis

A generative process giving rise to osteoclasts — specialized cells that break down bone tissue to remodel it.

Osteopenia

A condition characterized by lower bone density, but less severe than osteoporosis.

Ribosomopathy

A pathological condition resulting from defects in ribosome biogenesis or in the structure or function of ribosomes.

Sec61 translocon

A channel controlling the co-translational entry of nascent polypeptides destined for the secretory pathway into the lumen or across the membrane of the endoplasmic reticulum.

Signal recognition particle

A ribonucleoprotein complex that co-translationally recognizes a signal peptide in some proteins and targets the translating ribosome to the endoplasmic reticulum membrane.

TNBC

Triple-negative breast cancer is an aggressive tumour characterized by low or absent oestrogen, progesterone and human epidermal growth factor 2 (HER2) receptors.

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Acosta-Alvear, D., Harnoss, J.M., Walter, P. et al. Homeostasis control in health and disease by the unfolded protein response. Nat Rev Mol Cell Biol 26, 193–212 (2025). https://doi.org/10.1038/s41580-024-00794-0

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