Journal
CELL REPORTS
Volume 13, Issue 5, Pages 944-956Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.09.047
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Funding
- Ministry of Education
- NOVARTIS Foundation (Japan) for the Promotion of Science
- Uehara Memorial Foundation
- Daiichi Sankyo Foundation of Life Science
- Astellas Foundation for Research on Metabolic Disorders
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Suzuken Memorial Foundation
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [14J07625, 15H01539, 15K11080, 26114009] Funding Source: KAKEN
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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.
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