This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Upton, J.-P.
Right arrow Articles by Oakes, S. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Upton, J.-P.
Right arrow Articles by Oakes, S. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, June 2008, p. 3943-3951, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.00013-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Caspase-2 Cleavage of BID Is a Critical Apoptotic Signal Downstream of Endoplasmic Reticulum Stress{triangledown}

John-Paul Upton,1,{dagger} Kathryn Austgen,1,{dagger} Mari Nishino,1 Kristen M. Coakley,1 Andrew Hagen,2 Dan Han,2 Feroz R. Papa,2 and Scott A. Oakes1*

Departments of Pathology,1 Medicine, University of California, San Francisco, California 941432

Received 4 January 2008/ Returned for modification 6 February 2008/ Accepted 5 April 2008

The accumulation of misfolded proteins stresses the endoplasmic reticulum (ER) and triggers cell death through activation of the multidomain proapoptotic BCL-2 proteins BAX and BAK at the outer mitochondrial membrane. The signaling events that connect ER stress with the mitochondrial apoptotic machinery remain unclear, despite evidence that deregulation of this pathway contributes to cell loss in many human degenerative diseases. In order to "trap" and identify the apoptotic signals upstream of mitochondrial permeabilization, we challenged Bax–/– Bak–/– mouse embryonic fibroblasts with pharmacological inducers of ER stress. We found that ER stress induces proteolytic activation of the BH3-only protein BID as a critical apoptotic switch. Moreover, we identified caspase-2 as the premitochondrial protease that cleaves BID in response to ER stress and showed that resistance to ER stress-induced apoptosis can be conferred by inhibiting caspase-2 activity. Our work defines a novel signaling pathway that couples the ER and mitochondria and establishes a principal apoptotic effector downstream of ER stress.

* Corresponding author. Mailing address: UCSF Department of Pathology, 513 Parnassus Avenue, HSW-517, Box 0511, San Francisco, CA 94143-0511. Phone: (415) 476-1777. Fax: (415) 514-3165. E-mail: scott.oakes{at}ucsf.edu

{triangledown} Published ahead of print on 21 April 2008.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, June 2008, p. 3943-3951, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.00013-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Xu, D., Perez, R. E., Rezaiekhaligh, M. H., Bourdi, M., Truog, W. E. (2009). Knockdown of ERp57 increases BiP/GRP78 induction and protects against hyperoxia and tunicamycin-induced apoptosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 297: L44-L51 [Abstract] [Full Text]  
  • Huang, W.-C., Lin, Y.-S., Chen, C.-L., Wang, C.-Y., Chiu, W.-H., Lin, C.-F. (2009). Glycogen Synthase Kinase-3{beta} Mediates Endoplasmic Reticulum Stress-Induced Lysosomal Apoptosis in Leukemia. J. Pharmacol. Exp. Ther. 329: 524-531 [Abstract] [Full Text]  
  • Shawgo, M. E., Shelton, S. N., Robertson, J. D. (2008). Caspase-mediated Bak Activation and Cytochrome c Release during Intrinsic Apoptotic Cell Death in Jurkat Cells. J. Biol. Chem. 283: 35532-35538 [Abstract] [Full Text]  
  • Troy, C. M., Ribe, E. M. (2008). Caspase-2: Vestigial Remnant or Master Regulator?. Sci Signal 1: pe42-pe42 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»