Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis

doi:10.1083/jcb.200302084

Published 7 July 2003. doi:10.1083/jcb.200302084

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Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis

Wei-Xing Zong¹, Chi Li¹, Georgia Hatzivassiliou¹, Tullia Lindsten², Qian-Chun Yu², Junying Yuan³ and Craig B. Thompson¹

¹ Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104
² Department of Pathology and Laboratory Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104
³ Department of Cell Biology, Harvard Medical School, Boston, MA 02115

Address correspondence to Craig B. Thompson, Department of Cancer Biology, Abramson Cancer Center, 421 Curie Blvd., BRB II/III, 445, Philadelphia, PA 19104-6160. Tel.: (215) 746-5515. Fax: (215) 746-5511. E-mail: craig{at}mail.med.upenn.edu

Bax and Bak play a redundant but essential role in apoptosisinitiated by the mitochondrial release of apoptogenic factors.In addition to their presence at the mitochondrial outer membrane,Bax and Bak can also localize to the ER. Agents that initiateER stress responses can induce conformational changes and oligomerizationof Bax on the ER as well as on mitochondria. In wild-type cells,this is associated with caspase 12 cleavage that is abolishedin bax^-^/^-bak^-^/^- cells. In bax^-^/^-bak^-^/^- cells, introduction ofBak mutants selectively targeted to either mitochondria or theER can induce apoptosis. However, ER-targeted, but not mitochondria-targeted,Bak leads to progressive depletion of ER Ca²⁺ and induces caspase12 cleavage. In contrast, mitochondria-targeted Bak leads toenhanced caspase 7 and PARP cleavage in comparison with theER-targeted Bak. These findings demonstrate that in additionto their functions at mitochondria, Bax and Bak also localizeto the ER and function to initiate a parallel pathway of caspaseactivation and apoptosis.

Key Words: Bak; Bax; Ca²⁺; caspase 12; ER

W.-X. Zong and C. Li contributed equally to this work.

^* Abbreviations used in this paper: BMH, bismaleimidohexane; cb5,cytochrome b5; HM, heavy membrane; IRES, internal ribosomalentry site; LM, light membrane; MEF, murine embryonic fibroblast;t-caspase, truncated caspase; UPR, unfolded protein response.

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