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

Hisae Kadowaki, Atsushi Nagai, Takeshi Maruyama, Yasunari Takami, Pasjan Satrimafitrah, Hironori Kato, Arata Honda, Tomohisa Hatta, Tohru Natsume, Takashi Sato, Hirofumi Kai, Hidenori Ichijo, Hideki Nishitoh

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)944-956
Number of pages13
JournalCell Reports
Volume13
Issue number5
DOIs
Publication statusPublished - 2015 Nov 3
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kadowaki, H., Nagai, A., Maruyama, T., Takami, Y., Satrimafitrah, P., Kato, H., Honda, A., Hatta, T., Natsume, T., Sato, T., Kai, H., Ichijo, H., & Nishitoh, H. (2015). Pre-emptive Quality Control Protects the ER from Protein Overload via the Proximity of ERAD Components and SRP. Cell Reports, 13(5), 944-956. https://doi.org/10.1016/j.celrep.2015.09.047