Early Events in the Endoplasmic Reticulum Unfolded Protein Response

Overview

Journal Cold Spring Harb Perspect Biol

Specialties Biology
Molecular Biology

Date 2018 Nov 7

PMID 30396883

Citations 83

Authors

Steffen Preissler

David Ron

Affiliations

Soon will be listed here.

Abstract

The physiological consequences of the unfolded protein response (UPR) are mediated by changes in gene expression. Underlying them are rapid processes involving preexisting components. We review recent insights gained into the regulation of the endoplasmic reticulum (ER) Hsp70 chaperone BiP, whose incorporation into inactive oligomers and reversible AMPylation and de-AMPylation present a first line of response to fluctuating levels of unfolded proteins. BiP activity is tied to the regulation of the UPR transducers by a recently discovered cycle of ER-localized, J protein-mediated formation of a repressive IRE1-BiP complex, whose working we contrast to an alternative model for UPR regulation that relies on direct recognition of unfolded proteins. We conclude with a discussion of mechanisms that repress messenger RNA (mRNA) translation to limit the flux of newly synthesized proteins into the ER, a rapid adaptation that does not rely on new macromolecule biosynthesis.

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References

Abastado J, Miller P, Jackson B, Hinnebusch A . Suppression of ribosomal reinitiation at upstream open reading frames in amino acid-starved cells forms the basis for GCN4 translational control. Mol Cell Biol. 1991; 11(1):486-96. PMC: 359655. DOI: 10.1128/mcb.11.1.486-496.1991. View

Sanyal A, Chen A, Nakayasu E, Lazar C, Zbornik E, Worby C . A novel link between Fic (filamentation induced by cAMP)-mediated adenylylation/AMPylation and the unfolded protein response. J Biol Chem. 2015; 290(13):8482-99. PMC: 4375499. DOI: 10.1074/jbc.M114.618348. View

Kimata Y, Oikawa D, Shimizu Y, Ishiwata-Kimata Y, Kohno K . A role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1. J Cell Biol. 2004; 167(3):445-56. PMC: 2172501. DOI: 10.1083/jcb.200405153. View

Shi Y, Vattem K, Sood R, An J, Liang J, Stramm L . Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol. 1998; 18(12):7499-509. PMC: 109330. DOI: 10.1128/MCB.18.12.7499. View

Sundaram A, Plumb R, Appathurai S, Mariappan M . The Sec61 translocon limits IRE1α signaling during the unfolded protein response. Elife. 2017; 6. PMC: 5449187. DOI: 10.7554/eLife.27187. View

Preissler S, Rato C, Chen R, Antrobus R, Ding S, Fearnley I . AMPylation matches BiP activity to client protein load in the endoplasmic reticulum. Elife. 2015; 4:e12621. PMC: 4739761. DOI: 10.7554/eLife.12621. View

Hollien J, Lin J, Li H, Stevens N, Walter P, Weissman J . Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol. 2009; 186(3):323-31. PMC: 2728407. DOI: 10.1083/jcb.200903014. View

Travers K, Patil C, Wodicka L, Lockhart D, Weissman J, Walter P . Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell. 2000; 101(3):249-58. DOI: 10.1016/s0092-8674(00)80835-1. View

Shi Y, Mosser D, Morimoto R . Molecular chaperones as HSF1-specific transcriptional repressors. Genes Dev. 1998; 12(5):654-66. PMC: 316571. DOI: 10.1101/gad.12.5.654. View

10.

Hollien J, Weissman J . Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science. 2006; 313(5783):104-7. DOI: 10.1126/science.1129631. View

11.

Wieteska L, Shahidi S, Zhuravleva A . Allosteric fine-tuning of the conformational equilibrium poises the chaperone BiP for post-translational regulation. Elife. 2017; 6. PMC: 5655141. DOI: 10.7554/eLife.29430. View

12.

Reid D, Chen Q, Tay A, Shenolikar S, Nicchitta C . The unfolded protein response triggers selective mRNA release from the endoplasmic reticulum. Cell. 2014; 158(6):1362-1374. PMC: 4163055. DOI: 10.1016/j.cell.2014.08.012. View

13.

Preissler S, Rato C, Perera L, Saudek V, Ron D . FICD acts bifunctionally to AMPylate and de-AMPylate the endoplasmic reticulum chaperone BiP. Nat Struct Mol Biol. 2016; 24(1):23-29. PMC: 5221731. DOI: 10.1038/nsmb.3337. View

14.

Tomoyasu T, Ogura T, Tatsuta T, Bukau B . Levels of DnaK and DnaJ provide tight control of heat shock gene expression and protein repair in Escherichia coli. Mol Microbiol. 1998; 30(3):567-81. DOI: 10.1046/j.1365-2958.1998.01090.x. View

15.

Crespillo-Casado A, Chambers J, Fischer P, Marciniak S, Ron D . PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz. Elife. 2017; 6. PMC: 5429092. DOI: 10.7554/eLife.26109. View

16.

Lin W, Kunkler P, Harding H, Ron D, Kraig R, Popko B . Enhanced integrated stress response promotes myelinating oligodendrocyte survival in response to interferon-gamma. Am J Pathol. 2008; 173(5):1508-17. PMC: 2570140. DOI: 10.2353/ajpath.2008.080449. View

17.

Preissler S, Chambers J, Crespillo-Casado A, Avezov E, Miranda E, Perez J . Physiological modulation of BiP activity by trans-protomer engagement of the interdomain linker. Elife. 2015; 4:e08961. PMC: 4608358. DOI: 10.7554/eLife.08961. View

18.

Lau E, Cao Q, Ng D, Bleakley B, Dincer T, Bot B . A large dataset of protein dynamics in the mammalian heart proteome. Sci Data. 2016; 3:160015. PMC: 4792174. DOI: 10.1038/sdata.2016.15. View

19.

Pincus D, Chevalier M, Aragon T, van Anken E, Vidal S, El-Samad H . BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response. PLoS Biol. 2010; 8(7):e1000415. PMC: 2897766. DOI: 10.1371/journal.pbio.1000415. View

20.

Hendershot L, Ting J, Lee A . Identity of the immunoglobulin heavy-chain-binding protein with the 78,000-dalton glucose-regulated protein and the role of posttranslational modifications in its binding function. Mol Cell Biol. 1988; 8(10):4250-6. PMC: 365497. DOI: 10.1128/mcb.8.10.4250-4256.1988. View