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PMID:26565908

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Citation

Kadowaki, H, Nagai, A, Maruyama, T, Takami, Y, Satrimafitrah, P, Kato, H, Honda, A, Hatta, T, Natsume, T, Sato, T, Kai, H, Ichijo, H and Nishitoh, H (2015) Pre-emptive Quality Control Protects the ER from Protein Overload via the Proximity of ERAD Components and SRP. Cell Rep 13:944-56

Abstract

Cells possess ER quality control systems to adapt to ER stress and maintain their function. ER-stress-induced pre-emptive quality control (ER pQC) selectively degrades ER proteins via translocational attenuation during ER stress. However, the molecular mechanism underlying this process remains unclear. Here, we find that most newly synthesized endogenous transthyretin proteins are rerouted to the cytosol without cleavage of the signal peptide, resulting in proteasomal degradation in hepatocytes during ER stress. Derlin family proteins (Derlins), which are ER-associated degradation components, reroute specific ER proteins, but not ER chaperones, from the translocon to the proteasome through interactions with the signal recognition particle (SRP). Moreover, the cytosolic chaperone Bag6 and the AAA-ATPase p97 contribute to the degradation of ER pQC substrates. These findings demonstrate that Derlins-mediated substrate-specific rerouting and Bag6- and p97-mediated effective degradation contribute to the maintenance of ER homeostasis without the need for translocation.

Links

PubMed Online version:10.1016/j.celrep.2015.09.047

Keywords

Amino Acid Sequence; Endoplasmic Reticulum Stress; Endoplasmic Reticulum-Associated Degradation; HEK293 Cells; Hep G2 Cells; Humans; Membrane Proteins/metabolism; Molecular Chaperones/metabolism; Molecular Sequence Data; Signal Recognition Particle/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:BAG6

involved_in

GO:0030433: ubiquitin-dependent ERAD pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BAG6

involved_in

GO:0010498: proteasomal protein catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BAG6

involved_in

GO:0061857: endoplasmic reticulum stress-induced pre-emptive quality control

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DERL3

enables

GO:0005047: signal recognition particle binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DERL3

enables

GO:0044877: protein-containing complex binding

ECO:0000353: physical interaction evidence used in manual assertion

GO:0005785

F

Seeded From UniProt

complete

HUMAN:DERL1

enables

GO:0005047: signal recognition particle binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DERL1

enables

GO:0044877: protein-containing complex binding

ECO:0000353: physical interaction evidence used in manual assertion

GO:0005785

F

Seeded From UniProt

complete

HUMAN:DERL2

enables

GO:0005047: signal recognition particle binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DERL2

enables

GO:0044877: protein-containing complex binding

ECO:0000353: physical interaction evidence used in manual assertion

GO:0005785

F

Seeded From UniProt

complete

HUMAN:TERA

involved_in

GO:0061857: endoplasmic reticulum stress-induced pre-emptive quality control

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TERA

involved_in

GO:0010498: proteasomal protein catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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