Ceapins block the unfolded protein response sensor ATF6α by inducing a neomorphic inter-organelle tether.

Autor:	Torres SE; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States., Gallagher CM; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States., Plate L; Department of Chemistry, Vanderbilt University, Nashville, United States.; Department of Biological Sciences, Vanderbilt University, Nashville, United States., Gupta M; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States., Liem CR; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States., Guo X; Department of Biochemistry and Biophysics, Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, United States.; Chan Zuckerberg Biohub, San Francisco, United States., Tian R; Department of Biochemistry and Biophysics, Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, United States.; Chan Zuckerberg Biohub, San Francisco, United States., Stroud RM; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States., Kampmann M; Department of Biochemistry and Biophysics, Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, United States.; Chan Zuckerberg Biohub, San Francisco, United States., Weissman JS; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States., Walter P; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2019 May 31; Vol. 8. Date of Electronic Publication: 2019 May 31.
DOI:	10.7554/eLife.46595
Abstrakt:	The unfolded protein response (UPR) detects and restores deficits in the endoplasmic reticulum (ER) protein folding capacity. Ceapins specifically inhibit the UPR sensor ATF6α, an ER-tethered transcription factor, by retaining it at the ER through an unknown mechanism. Our genome-wide CRISPR interference (CRISPRi) screen reveals that Ceapins function is completely dependent on the ABCD3 peroxisomal transporter. Proteomics studies establish that ABCD3 physically associates with ER-resident ATF6α in cells and in vitro in a Ceapin-dependent manner. Ceapins induce the neomorphic association of ER and peroxisomes by directly tethering the cytosolic domain of ATF6α to ABCD3's transmembrane regions without inhibiting or depending on ABCD3 transporter activity. Thus, our studies reveal that Ceapins function by chemical-induced misdirection which explains their remarkable specificity and opens up new mechanistic routes for drug development and synthetic biology. Competing Interests: ST, CG, LP, MG, CL, XG, RT, RS, MK, JW, PW No competing interests declared (© 2019, Torres et al.)
Databáze:	MEDLINE
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