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Druggable sensors of the unfolded protein response

Nature Chemical Biology volume 10, pages 892–901 (2014)Cite this article

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Abstract

The inability of cells to properly fold, modify and assemble secretory and transmembrane proteins leads to accumulation of misfolded proteins in the endoplasmic reticulum (ER). Under these conditions of 'ER stress', cell survival depends on homeostatic benefits from an intracellular signaling pathway called the unfolded protein response (UPR). When activated, the UPR induces transcriptional and translational programs that restore ER homeostasis. However, under high-level or chronic ER stress, these adaptive changes ultimately become overshadowed by alternative 'terminal UPR' signals that actively commit cells to degeneration, culminating in programmed cell death. Chronic ER stress and maladaptive UPR signaling are implicated in the etiology and pathogenesis of myriad human diseases. Naturally, this has generated widespread interest in targeting key nodal components of the UPR as therapeutic strategies. Here we summarize the state of this field with emphasis placed on two of the master UPR regulators, PERK and IRE1, which are both capable of being drugged with small molecules.

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Figure 1: The three arms of the UPR.
Figure 2: Adaptive signaling in the UPR.
Figure 3: Domain architecture of IRE1 and PERK.
Figure 4: Terminal signaling in the UPR.
Figure 5: Small-molecule modulators of PERK and IRE1α.
Figure 6: Modes of pharmacological modulation of IRE1a.

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Acknowledgements

This work was supported by the US National Institutes of Health grants DP2OD001925 (F.R.P.), RO1DK080955 (F.R.P.), P30DK063720 (F.R.P.), UO1DK089541 (F.R.P.), R01DK100623 (F.R.P. and D.J.M.), R01GM086858 (D.J.M.); the Burroughs Wellcome Foundation (F.R.P.); the Juvenile Diabetes Research Foundation (F.R.P.); the Harrington Discovery Institute Scholar-Innovator Award (F.R.P.); the Alfred P. Sloan Foundation (D.J.M.); and the Camille and Henry Dreyfus Foundation (D.J.M.).

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Authors and Affiliations

  1. Department of Chemistry, University of Washington, Seattle, Seattle, Washington, USA

    Dustin J Maly

  2. Department of Medicine, University of California–San Francisco, San Francisco, California, USA

    Feroz R Papa

  3. Diabetes Center, University of California–San Francisco, San Francisco, California, USA

    Feroz R Papa

  4. Lung Biology Center, University of California–San Francisco, San Francisco, California, USA

    Feroz R Papa

  5. California Institute for Quantitative Biosciences, University of California–San Francisco, San Francisco, California, USA

    Feroz R Papa

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Correspondence to Dustin J Maly or Feroz R Papa.

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Maly, D., Papa, F. Druggable sensors of the unfolded protein response. Nat Chem Biol 10, 892–901 (2014). https://doi.org/10.1038/nchembio.1664

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