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Hsp83 loss suppresses proteasomal activity resulting in an upregulation of caspase-dependent compensatory autophagy

Choutka, Courtney and DeVorkin, Lindsay and Go, Nancy Erro and Hou, Ying-Chen Claire and Moradian, Annie and Morin, Gregg B. and Gorski, Sharon M. (2017) Hsp83 loss suppresses proteasomal activity resulting in an upregulation of caspase-dependent compensatory autophagy. Autophagy, 13 (9). pp. 1573-1589. ISSN 1554-8627.

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The 2 main degradative pathways that contribute to proteostasis are the ubiquitin-proteasome system and autophagy but how they are molecularly coordinated is not well understood. Here, we demonstrate an essential role for an effector caspase in the activation of compensatory autophagy when proteasomal activity is compromised. Functional loss of Hsp83, the Drosophila ortholog of human HSP90 (heat shock protein 90), resulted in reduced proteasomal activity and elevated levels of the effector caspase Dcp-1. Surprisingly, genetic analyses showed that the caspase was not required for cell death in this context, but instead was essential for the ensuing compensatory autophagy, female fertility, and organism viability. The zymogen pro-Dcp-1 was found to interact with Hsp83 and undergo proteasomal regulation in an Hsp83-dependent manner. Our work not only reveals unappreciated roles for Hsp83 in proteasomal activity and regulation of Dcp-1, but identifies an effector caspase as a key regulatory factor for sustaining adaptation to cell stress in vivo.

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Moradian, Annie0000-0002-0407-2031
Additional Information:© 2017 Courtney Choutka, Lindsay DeVorkin, Nancy Erro Go, Ying-Chen Claire Hou, Annie Moradian, Gregg B. Morin, and Sharon M. Gorski. Published with license by Taylor & Francis. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. Received 12 Jan 2017, Accepted 01 Jun 2017, Published online: 14 Aug 2017. The authors would like to thank members of the Gorski laboratory and L. Megeney for helpful discussions, and S. Bortnik and V. Dreizen for assistance in puncta quantitfication. They would also like to thank K. McCall, B. Edgar, P. Meier, U. Pandey, Bloomington Stock Center and VDRC stock center for reagents, G. Sharma for flow cytometry assistance and T. Heslip, C. Soong and D. Luciani for confocal microscope access and support. This work was supported by a CIHR Operating Grant (MOP-78882) to SMG and GBM, and a NSERC Operating Grant (RGPIN/04982–2015) to SMG. SMG was supported in part by a CIHR New Investigator Salary Award. CC was supported in part by a NSERC Doctoral Postgraduate Scholarship. No potential conflicts of interest were disclosed.
Funding AgencyGrant Number
Canadian Institutes of Health Research (CIHR)MOP-78882
Natural Sciences and Engineering Research Council of Canada (NSERC)RGPIN/04982-2015
Subject Keywords:apoptosis, caspase, compensatory autophagy, Dcp-1, Drosophila, heat-shock protein, Hsp83, ubiquitin-proteasome system
Issue or Number:9
Record Number:CaltechAUTHORS:20170822-072225587
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:80664
Deposited By: Ruth Sustaita
Deposited On:22 Aug 2017 19:09
Last Modified:22 Nov 2019 09:58

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