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Cell Rep. 2015 Nov 3;13(5):944-56. doi: 10.1016/j.celrep.2015.09.047. Epub 2015 Oct 22.

Pre-emptive Quality Control Protects the ER from Protein Overload via the Proximity of ERAD Components and SRP.

Author information

1
Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan; Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Center of Excellence Program, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
2
Center of Excellence Program, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
3
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Center of Excellence Program, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
4
Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
5
Organization for Promotion of Tenure Track, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
6
Biological Systems Control Team, Biomedicinal Information Research Center, National Institutes of Advanced Industrial Science and Technology, 2-42 Aomi, Koto-ku, Tokyo 135-0064, Japan.
7
Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
8
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
9
Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan; Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Center of Excellence Program, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan. Electronic address: nishitoh@med.miyazaki-u.ac.jp.

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.

PMID:
26565908
DOI:
10.1016/j.celrep.2015.09.047
[Indexed for MEDLINE]
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