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Emerging functions of the unfolded protein response in immunity

Nature Immunology volume 15, pages 910–919 (2014)Cite this article

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Abstract

The unfolded protein response (UPR) has traditionally been viewed as an adaptive response triggered by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and aimed at restoring ER function. The UPR can also be an anticipatory response that is activated well before the disruption of protein homeostasis. UPR signaling intersects at many levels with the innate and adaptive immune responses. In some types of cells of the immune system, such as dendritic cells (DCs) and B cells, particular sensors that detect the UPR seem to be constitutively active in the absence of induction of the traditional UPR gene program and are necessary for antigen presentation and immunoglobulin synthesis. The UPR also influences signaling via Toll-like receptors (TLRs) and activation of the transcription factor NF-κB, and some pathogens subvert the UPR. This Review summarizes these emerging noncanonical functions of the UPR in immunity.

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Figure 1: Three different sensors jointly coordinate the UPR in mammals.

Kim Caesar/Nature Publishing Group

Figure 2: The evolution of the UPR shows conserved functions in immune responses.

Kim Caesar/Nature Publishing Group

Figure 3: IRE-1 intersects with inflammatory pathways.

Kim Caesar/Nature Publishing Group

Figure 4: Pathways downstream of PERK are tightly controlled by inflammatory signals.

Kim Caesar/Nature Publishing Group

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Acknowledgements

We thank F. Martinon, P. de Bleser, P. Hulpiau and L. Martens for comments on the bioinformatics analysis. Supported by the European Research Council (B.N.L.), Fonds Wetenschappelijk Onderzoek (B.N.L. and S.J.), University of Ghent Multidisciplinary Research Platform (B.N.L and S.J.), the US National Institutes of Health (R37 DK057665, R37 AI048638, U19 AI090023 and U19 AI057266 to B.P.) and the Bill & Melinda Gates Foundation (B.P.).

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Authors and Affiliations

  1. Unit Immunoregulation and Mucosal Immunology, VIB Inflammation Research Centre, Ghent, Belgium

    Sophie Janssens & Bart N Lambrecht

  2. Ghent Researchers on Unfolded Proteins in Inflammation and Disease Consortium, Ghent University and University Hospital, Ghent, Belgium

    Sophie Janssens & Bart N Lambrecht

  3. Department of Respiratory Medicine, Ghent University, Ghent, Belgium

    Sophie Janssens & Bart N Lambrecht

  4. Department of Pathology, Emory Vaccine Center, Yerkes National Primate Center, Emory University, Atlanta, Georgia

    Bali Pulendran

  5. Department of Pulmonary Medicine, ErasmusMC, Rotterdam, the Netherlands

    Bart N Lambrecht

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  1. Sophie Janssens
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Correspondence to Bart N Lambrecht.

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Janssens, S., Pulendran, B. & Lambrecht, B. Emerging functions of the unfolded protein response in immunity. Nat Immunol 15, 910–919 (2014). https://doi.org/10.1038/ni.2991

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