Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity

Haller, M., Hock, A. K., Giampazolias, E., Oberst, A., Green, D. R., Debnath, J., Ryan, K. M. , Vousden, K. H. and Tait, S. W. G. (2014) Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity. Autophagy, 10(12), pp. 2269-2278. (doi:10.4161/15548627.2014.981914) (PMID:25629932)

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Abstract

During macroautophagy, conjugation of ATG12 to ATG5 is essential for LC3 lipidation and autophagosome formation. Additionally, ATG12 has ATG5-independent functions in diverse processes including mitochondrial fusion and mitochondrial-dependent apoptosis. In this study, we investigated the regulation of free ATG12. In stark contrast to the stable ATG12–ATG5 conjugate, we find that free ATG12 is highly unstable and rapidly degraded in a proteasome-dependent manner. Surprisingly, ATG12, itself a ubiquitin-like protein, is directly ubiquitinated and this promotes its proteasomal degradation. As a functional consequence of its turnover, accumulation of free ATG12 contributes to proteasome inhibitor-mediated apoptosis, a finding that may be clinically important given the use of proteasome inhibitors as anticancer agents. Collectively, our results reveal a novel interconnection between autophagy, proteasome activity, and cell death mediated by the ubiquitin-like properties of ATG12.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ryan, Professor Kevin and Vousden, Karen and Tait, Professor Stephen and Hock, Dr Andreas and Haller, Ms Martina
Authors: Haller, M., Hock, A. K., Giampazolias, E., Oberst, A., Green, D. R., Debnath, J., Ryan, K. M., Vousden, K. H., and Tait, S. W. G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Autophagy
Publisher:Taylor and Francis
ISSN:1554-8627
ISSN (Online):1554-8635
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Autophagy 10(12):2269-2278
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
607521A new approach to understanding mitochondrial functions in cell death, autophagy and beyondStephen TaitBiotechnology and Biological Sciences Research Council (BBSRC)BB/K008374/1RI CANCER SCIENCES