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) (PMCID:PMC4502749)

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 Hock, Dr Andreas and Haller, Ms Martina and Vousden, Karen and Tait, Professor Stephen
• 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 > School 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
60752	1	A new approach to understanding mitochondrial functions in cell death, autophagy and beyond	Stephen Tait	Biotechnology and Biological Sciences Research Council (BBSRC)	BB/K008374/1	RI CANCER SCIENCES