Title

Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response

Document Type

Journal Article

Faculty

Faculty of Computing, Health and Science

School

School of Natural Sciences / Centre for Ecosystem Management

RAS ID

14137

Comments

This article was originally published as: McKibbin, C., Mares, A., Piacenti, M., Williams, H., Roboti, P., Puumalainen, M., Callan, A. C., Lesiak-Mieczkowska, K., Linder, S., Harant, H., High, S., Flitsch, S., Whitehead, R., & Swanton, E. (2012). Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response. Biochemical Journal, 442(3), 639-648. Original article available here

Abstract

Selective small-molecule inhibitors represent powerful tools for the dissection of complex biological processes. ESI (eeyarestatin I) is a novel modulator of ER (endoplasmic reticulum) function. In the present study, we show that in addition to acutely inhibiting ERAD (ER-associated degradation), ESI causes production of mislocalized polypeptides that are ubiquitinated and degraded. Unexpectedly, our results suggest that these non-translocated polypeptides promote activation of the UPR (unfolded protein response), and indeed we can recapitulate UPR activation with an alternative and quite distinct inhibitor of ER translocation. These results suggest that the accumulation of non-translocated proteins in the cytosol may represent a novel mechanism that contributes to UPR activation.

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