Non-canonical function of Bax in stress-induced nuclear protein redistribution
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Cellular and Molecular Life Sciences
RESEARCH ARTICLE
Non-canonical function of Bax in stress-induced nuclear protein redistribution Liora Lindenboim · Elisa Ferrando-May · Christoph Borner · Reuven Stein
Received: 11 September 2012 / Revised: 13 February 2013 / Accepted: 18 February 2013 / Published online: 9 March 2013 © Springer Basel 2013
Abstract Bax and Bak (Bax/Bak) are essential pro-apoptotic proteins of the Bcl-2 family that trigger mitochondrial outer membrane permeabilization (MOMP) in a Bcl-2/ Bcl-xL-inhibitable manner. We recently discovered a new stress-related function for Bax/Bak—regulation of nuclear protein redistribution (NPR) from the nucleus to cytoplasm. This effect was independent of Bax/Bak N-terminus exposure and not inhibited by Bcl-xL over-expression. Here, we studied the molecular mechanism governing this novel noncanonical response. Wild-type (WT) and mutant versions of Bax were re-expressed in Bax/Bak double-knockout mouse
Electronic supplementary material The online version of this article (doi:10.1007/s00018-013-1306-4) contains supplementary material, which is available to authorized users. L. Lindenboim · R. Stein (*) Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Ramat Aviv, Israel e-mail: [email protected] E. Ferrando-May Department of Biology, Bioimaging Center, University of Konstanz, 78457 Constance, Germany C. Borner Institute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, Stefan Meier Strasse 17, 79104 Freiburg, Germany C. Borner Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Albertstrasse 19a, 79104 Freiburg, Germany C. Borner Excellence Cluster, Centre for Biological Signaling Studies (BIOSS), Albert Ludwigs University Freiburg, Hebelstrasse 25, 79104 Freiburg, Germany
embryonic fibroblasts and their ability to promote NPR, apoptotic events, and changes in lamin A mobility was examined. Our results show that, in this system, Bax expression was sufficient to restore NPR such as in WT cells undergoing apoptosis. This activity of Bax was uncoupled from cytochrome c release from the mitochondria (indicative of MOMP) and required its membrane localization, α helices 5/6, and the Bcl-2 homology 3 (BH3) domain. Moreover, enrichment of Bax in the nuclear envelope by the so-called Klarsicht/ANC-1/Syne-1 homology domain effectively triggered NPR as in WT Bax, but without inducing MOMP or cell death. Bax-induced NPR was associated with impairment in lamin A mobility, implying a connection between these two nuclear envelope-associated events. Overall, the results indicate a new MOMP-independent, stress-induced Bax function on the nuclear envelope. Keywords Apoptosis · Bcl-2 proteins · Nucleus · Nuclear permeability Abbreviations Bax/Bak Bax and Bak DKO Double-knockout DMEM Dulbecco’s modified Eagle’s medium FRAP Fluorescence recovery after photobleaching GAPDH Glyceraldehyde 3-phosphate dehydrogenase GFP Green fluorescent protein HA Hemag
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