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 Hu, P.
Right arrow Articles by Exton, J. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hu, P.
Right arrow Articles by Exton, J. H.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, April 2006, p. 3071-3084, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3071-3084.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Autocrine Tumor Necrosis Factor Alpha Links Endoplasmic Reticulum Stress to the Membrane Death Receptor Pathway through IRE1{alpha}-Mediated NF-{kappa}B Activation and Down-Regulation of TRAF2 Expression

Ping Hu,1,{dagger} Zhang Han,1,{dagger} Anthony D. Couvillon,1 Randal J. Kaufman,2 and John H. Exton1*

Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232,1 Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 481092

Received 9 August 2005/ Returned for modification 10 September 2005/ Accepted 20 January 2006

NF-{kappa}B is critical for determining cellular sensitivity to apoptotic stimuli by regulating both mitochondrial and death receptor apoptotic pathways. The endoplasmic reticulum (ER) emerges as a new apoptotic signaling initiator. However, the mechanism by which ER stress activates NF-{kappa}B and its role in regulation of ER stress-induced cell death are largely unclear. Here, we report that, in response to ER stress, IKK forms a complex with IRE1{alpha} through the adapter protein TRAF2. ER stress-induced NF-{kappa}B activation is impaired in IRE1{alpha} knockdown cells and IRE1{alpha}–/– MEFs. We found, however, that inhibiting NF-{kappa}B significantly decreased ER stress-induced cell death in a caspase-8-dependent manner. Gene expression analysis revealed that ER stress-induced expression of tumor necrosis factor alpha (TNF-{alpha}) was IRE1{alpha} and NF-{kappa}B dependent. Blocking TNF receptor 1 signaling significantly inhibited ER stress-induced cell death. Further studies suggest that ER stress induces down-regulation of TRAF2 expression, which impairs TNF-{alpha}-induced activation of NF-{kappa}B and c-Jun N-terminal kinase and turns TNF-{alpha} from a weak to a powerful apoptosis inducer. Thus, ER stress induces two signals, namely TNF-{alpha} induction and TRAF2 down-regulation. They work in concert to amplify ER-initiated apoptotic signaling through the membrane death receptor.

* Corresponding author. Mailing address: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 702 Light Hall, Nashville, TN 37232-0615. Phone: (615) 322-6494. Fax: (615) 322-4381. E-mail: john.exton{at}vanderbilt.edu.

{dagger} P.H. and Z.H. contributed equally to this work.

Molecular and Cellular Biology, April 2006, p. 3071-3084, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3071-3084.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Harama, D., Koyama, K., Mukai, M., Shimokawa, N., Miyata, M., Nakamura, Y., Ohnuma, Y., Ogawa, H., Matsuoka, S., Paton, A. W., Paton, J. C., Kitamura, M., Nakao, A. (2009). A Subcytotoxic Dose of Subtilase Cytotoxin Prevents Lipopolysaccharide-Induced Inflammatory Responses, Depending on its Capacity to Induce the Unfolded Protein Response. J. Immunol. 183: 1368-1374 [Abstract] [Full Text]  
  • Yamazaki, H., Hiramatsu, N., Hayakawa, K., Tagawa, Y., Okamura, M., Ogata, R., Huang, T., Nakajima, S., Yao, J., Paton, A. W., Paton, J. C., Kitamura, M. (2009). Activation of the Akt-NF-{kappa}B Pathway by Subtilase Cytotoxin through the ATF6 Branch of the Unfolded Protein Response. J. Immunol. 183: 1480-1487 [Abstract] [Full Text]  
  • Shi, Y., Porter, K., Parameswaran, N., Bae, H. K., Pestka, J. J. (2009). Role of GRP78/BiP Degradation and ER Stress in Deoxynivalenol-Induced Interleukin-6 Upregulation in the Macrophage. Toxicol Sci 109: 247-255 [Abstract] [Full Text]  
  • Hayakawa, K., Hiramatsu, N., Okamura, M., Yamazaki, H., Nakajima, S., Yao, J., Paton, A. W., Paton, J. C., Kitamura, M. (2009). Acquisition of Anergy to Proinflammatory Cytokines in Nonimmune Cells through Endoplasmic Reticulum Stress Response: A Mechanism for Subsidence of Inflammation. J. Immunol. 182: 1182-1191 [Abstract] [Full Text]  
  • Bian, Z.-M., Elner, S. G., Elner, V. M. (2008). Regulated Expression of Caspase-12 Gene in Human Retinal Pigment Epithelial Cells Suggests Its Immunomodulating Role. IOVS 49: 5593-5601 [Abstract] [Full Text]  
  • Lindenmeyer, M. T., Rastaldi, M. P., Ikehata, M., Neusser, M. A., Kretzler, M., Cohen, C. D., Schlondorff, D. (2008). Proteinuria and Hyperglycemia Induce Endoplasmic Reticulum Stress. J. Am. Soc. Nephrol. 19: 2225-2236 [Abstract] [Full Text]  
  • Okamura, M., Takano, Y., Hiramatsu, N., Hayakawa, K., Yao, J., Paton, A. W., Paton, J. C., Kitamura, M. (2008). Suppression of cytokine responses by indomethacin in podocytes: a mechanism through induction of unfolded protein response. Am. J. Physiol. Renal Physiol. 295: F1495-F1503 [Abstract] [Full Text]  
  • Pastorino, J. G., Shulga, N. (2008). Tumor Necrosis Factor-{alpha} Can Provoke Cleavage and Activation of Sterol Regulatory Element-binding Protein in Ethanol-exposed Cells via a Caspase-dependent Pathway That Is Cholesterol Insensitive. J. Biol. Chem. 283: 25638-25649 [Abstract] [Full Text]  
  • Kitamura, M. (2008). Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: Janus faces. Am. J. Physiol. Renal Physiol. 295: F323-F334 [Abstract] [Full Text]  
  • Luo, D., He, Y., Zhang, H., Yu, L., Chen, H., Xu, Z., Tang, S., Urano, F., Min, W. (2008). AIP1 Is Critical in Transducing IRE1-mediated Endoplasmic Reticulum Stress Response. J. Biol. Chem. 283: 11905-11912 [Abstract] [Full Text]  
  • Scheuner, D., Kaufman, R. J. (2008). The Unfolded Protein Response: A Pathway That Links Insulin Demand with {beta}-Cell Failure and Diabetes. Endocr. Rev. 29: 317-333 [Abstract] [Full Text]  
  • Eizirik, D. L., Cardozo, A. K., Cnop, M. (2008). The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus. Endocr. Rev. 29: 42-61 [Abstract] [Full Text]  
  • Gregor, M. F., Hotamisligil, G. S. (2007). Thematic review series: Adipocyte Biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J. Lipid Res. 48: 1905-1914 [Abstract] [Full Text]  
  • Tabata, Y., Takano, K., Ito, T., Iinuma, M., Yoshimoto, T., Miura, H., Kitao, Y., Ogawa, S., Hori, O. (2007). Vaticanol B, a resveratrol tetramer, regulates endoplasmic reticulum stress and inflammation. Am. J. Physiol. Cell Physiol. 293: C411-C418 [Abstract] [Full Text]  
  • Masud, A., Mohapatra, A., Lakhani, S. A., Ferrandino, A., Hakem, R., Flavell, R. A. (2007). Endoplasmic Reticulum Stress-induced Death of Mouse Embryonic Fibroblasts Requires the Intrinsic Pathway of Apoptosis. J. Biol. Chem. 282: 14132-14139 [Abstract] [Full Text]  
  • Gould, D. B., Reedy, M., Wilson, L. A., Smith, R. S., Johnson, R. L., John, S. W. M. (2006). Mutant Myocilin Nonsecretion In Vivo Is Not Sufficient To Cause Glaucoma. Mol. Cell. Biol. 26: 8427-8436 [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»