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The unfolded protein response in nutrient sensing and differentiation

Key Points

  • The endoplasmic reticulum (ER) is an important protein-folding compartment in the eukaryotic cell. All eukaryotic cells have a protective mechanism that permits adaptation to conditions that disrupt protein folding in the ER.

  • As required, cells have the ability to increase the ER protein-folding capacity and reduce the ER protein-folding load.

  • Three signal-transducers detect unfolded protein accumulation and transmit signals to increase transcription of a main subset of nuclear genes and to reduce the rate of polypeptide synthesis.

  • The ER-transmembrane protein ATF6 is cleaved on accumulation of unfolded proteins in the ER to release a cytosolic fragment that translocates to the nucleus to mediate transcriptional activation of the ER stress-response genes. In parallel, IRE1 is a protein kinase/endoribonuclease that is activated to induce splicing of a specific mRNA that encodes Hac1 in yeast and XBP1 in mammalian cells, and leads to transcriptional activation of the ER stress-response genes. In addition, PERK is a protein kinase that is activated to phosphorylate and inactivate the translation initiation factor eIF2.

  • Finally, recent studies support that cell differentiation that is associated with increased secretory-protein production are coupled with activation of these same signalling pathways that expand the ER protein-folding capacity and reduce its load. In addition, studies indicate that in some cases, these signalling pathways have evolved to couple nutritional requirements with metabolic processes.

Abstract

Eukaryotic cells coordinate protein-folding reactions in the endoplasmic reticulum with gene expression in the nucleus and messenger RNA translation in the cytoplasm. As the rate of protein synthesis increases, protein folding can be compromised, so cells have evolved signal-transduction pathways that control transcription and translation — the 'unfolded protein response'. Recent studies indicate that these pathways also coordinate rates of protein synthesis with nutrient and energy stores, and regulate cell differentiation to survive nutrient-limiting conditions or to produce large amounts of secreted products such as hormones, antibodies or growth factors.

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Figure 1: Use of energy during secretory protein biogenesis.
Figure 2: Domain structure of the three proximal sensors of the UPR.
Figure 3: Transcriptional activation by cleavage of ER-bound transcription factors.
Figure 4: Regulation of translation initiation through eIF2 phosphorylation.
Figure 5: Models for the UPR as a nutrient sensor that controls differentiation in yeast in response to nitrogen starvation.
Figure 6: Hypothesis for UPR transcriptional and translational control in pancreatic β-cell function.

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Acknowledgements

We gratefully thank present and past members of the Kaufman laboratory for contributing to ideas presented here. Portions of this work were supported by the National Institutes of Health.

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Correspondence to Randal J. Kaufman.

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DATABASES

Interpro

bZIP

serine/threonine kinase domain

LocusLink

ATF6

eIF2α

IRE1α

IRE1β

PDI

SCAP

OMIM

Crohn's disease

homocysteinemia

ulcerative colitis

Wolcott–Rallison syndrome

<i>Saccharomyces</i> Genome Database

DER1

Gcn2

GCN4

HAC1

HRD1

HRD3

Ime1

INO1

Ire1

KAR2

Opi1

Rme1

S1P

S2P

UBC7

NF-Y

Swiss-Prot

ATF4

ATF6α

ATF6β

CNX

CRT

ERp57

GLUT1

PERK/PEK

PKR

SREBP

XBP1

Wormbase

ire-1

xbp-1

Glossary

CHAPERONE

A protein that facilitates protein folding or promotes assembly of multisubunit complexes. Chaperones act by preventing aggregation of unassembled protein subunits or partially folded protein domains.

APOPTOSIS

Programmed cell death, characterized by death receptor ligand or mitochondria-elicited activation of caspase proteases, which leads to nuclear condensation, DNA fragmentation and clearance of the dead cell by surrounding tissue.

NECROSIS

A cell-death process that is characterized by an accompanying inflammatory response.

TYPE 1 TRANSMEMBRANE-RECEPTOR KINASE

A protein kinase that spans the plasma membrane once. Its topology is such that the carboxy-terminal end extends into the cytoplasm. These protein kinases are often activated by ligand-binding-induced dimerization.

RNASE L

A constitutively expressed, latent, non-specific endoribonuclease that is activated by 2′-5′ oligoladenylate. Interferon-α and β induce RNase L gene expression as part of the host antiviral response.

bZIP

A basic leucine zipper motif that is often associated with transcription factors. Dimerization through the leucine zipper is required for DNA binding. Hetero- or homodimers lend further complexity to the regulation of transcription by members of this family, which include Fos, Jun and the CREB/ATF family members.

TRANSFER RNA LIGASE

A cellular RNA ligase for splicing of transfer RNA intermediates. In general, tRNA ligase is detectable in complex with an endonuclease activity and a phosphotransferase to accomplish a complete splicing reaction. In yeast, tRNA ligase splices the 5′ and 3′ exons that are generated by the endoribonuclease activity of IRE1.

SPLICEOSOME

A ribonucleoprotein complex that is involved in splicing of nuclear pre-mRNA. It is composed of five small nuclear ribonucleoproteins (snRNPs) and more than 50 non-snRNPs, which recognize and assemble on exon–intron boundaries to catalyse intron processing of the pre-mRNA.

5′ UNTRANSLATED REGION

(5′ UTR). The 5′ region of an mRNA of variable length that does not contain protein-coding sequence, but can contain secondary structure or sequence information that affects the translation efficiency or stability of a transcript.

POLYRIBOSOME

An mRNA with several 80S subunits that actively translate proteins. A circular structure is formed by the association of the 3′ tail of the mRNA with the 5′ UTR through the interaction of RNA-binding proteins that function as translation-initiation factors.

MONOSOME

An 80S particle that contains a single mRNA, an 80S ribosome that is composed of the 40S and 60S ribosomal subunits, and translation-initiation factors.

INOSITOL PROTOTROPHY

A condition in which an organism can grow in the absence of inositol. In yeast, the deletion of the ER stress-signalling genes IRE1 or HAC1 decreases the biosynthetic capacity for inositol, which results in the need for inositol supplementation of the growth medium.

ONE-HYBRID SCREEN

An interaction screen in which only one partner involves a hybrid protein. For example, a complementary DNA library was prepared that had random cDNA fragments fused to a transcriptional-activation domain. Screening for hybrid proteins that activated transcription from an ERSE motif upstream of a β-galactosidase coding region identified ATF6 and XBP1 as ERSE-binding proteins.

L2 LARVAL STAGE

The second of four developmental stages of C. elegans larvae, from maturation to adulthood. The four stages are punctuated by moults. The germline begins development and extension during the L2 larval stage.

TUNICAMYCIN

A drug that potently and specifically inhibits N-linked glycosylation at the first stage of biosynthesis of the dolichol–oligosaccharide core donor structure. Treatment with tunicamycin leads to accumulation of unfolded protein in the ER because N-linked glycosylation is required for correct protein folding and to promote protein solubility.

RAG1/2

Immunoglobin heavy and light genes and T-cell-receptor genes are assembled from germ-line variable- and constant-region gene segments by a DNA recombination process in B and T cells, respectively. These gene rearrangements depend on the expression of recombination-activating genes (RAG)1 and 2.

HEXOKINASES

Hexokinases in most cells have a high affinity for glucose and transfer a phosphoryl group from ATP to glucose to form glucose-6-phosphate (G6P) for use in glycolysis. Pancreatic β cells mainly express glucokinase, which has a much lower affinity for glucose and forms G6P at a rate that is proportional to the concentration of glucose.

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Kaufman, R., Scheuner, D., Schröder, M. et al. The unfolded protein response in nutrient sensing and differentiation. Nat Rev Mol Cell Biol 3, 411–421 (2002). https://doi.org/10.1038/nrm829

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