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Regulatory crosstalk within the mammalian unfolded protein response

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Abstract

Increased demands on the protein folding capacity of the endoplasmic reticulum (ER) trigger the unfolded protein response (UPR). Comprised of a tripartite signaling system, the UPR regulates translation and gene transcription to manifest pro-adaptive and, if necessary, pro-apoptotic outcomes. The three UPR pathways, initiated by activating transcription factor 6, inositol requiring enzyme 1, and protein kinase RNA-activated-like ER kinase (PERK), direct distinct downstream signaling events. However, it is becoming increasingly clear that interplay between the cascades is vital in shaping the UPR. In particular, recent discoveries have revealed that PERK-dependent signals mediate both inter- and intra-pathway regulation within the UPR, underscoring the critical role of the PERK pathway in the cellular response to ER stress.

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Acknowledgments

The author apologizes to any investigators whose work in the UPR field was not cited due to the scope of this article. The author thanks Jason P. Clark (University of South Alabama) for expert technical assistance with artwork. J.W.B. was supported by a Grant from the US National Institutes of Health (GM061970).

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  1. Department of Molecular and Cellular Sciences, College of Osteopathic Medicine, Liberty University, 1971 University Boulevard, Lynchburg, VA, 24515, USA

    Joseph W. Brewer

  2. Department of Microbiology and Immunology, College of Medicine, University of South Alabama, 5851 USA Drive North, Mobile, AL, 36688, USA

    Joseph W. Brewer

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Brewer, J.W. Regulatory crosstalk within the mammalian unfolded protein response. Cell. Mol. Life Sci. 71, 1067–1079 (2014). https://doi.org/10.1007/s00018-013-1490-2

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  • DOI: https://doi.org/10.1007/s00018-013-1490-2

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