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Molecular and Cellular Biology, November 2007, p. 7394-7404, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00600-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

FADD Negatively Regulates Lipopolysaccharide Signaling by Impairing Interleukin-1 Receptor-Associated Kinase 1-MyD88 Interaction{triangledown}

Rachel Zhande,1,2 Shauna M. Dauphinee,1,4 James A. Thomas,5 Masahiro Yamamoto,6 Shizuo Akira,6 and Aly Karsan1,2,3,4*

Department of Medical Biophysics, British Columbia Cancer Agency,1 Department of Pathology and Laboratory Medicine, University of British Columbia,2 Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency,3 Experimental Medicine Program, University of British Columbia, Vancouver, BC, Canada,4 Departments of Pediatrics, Molecular Biology, and Oncology, University of Texas Southwestern Medical Center, Dallas, Texas,5 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and ERATO, Japan Science and Technology Agency, Osaka, Japan6

Received 5 April 2007/ Returned for modification 11 May 2007/ Accepted 25 August 2007

Lipopolysaccharide (LPS) engages Toll-like receptor 4 (TLR4) on various cells to initiate inflammatory and angiogenic pathways. FADD is an adaptor protein involved in death receptor-mediated apoptosis. Here we report a role for FADD in regulation of TLR4 signals in endothelial cells. FADD specifically attenuates LPS-induced activation of c-Jun NH2-terminal kinase and phosphatidylinositol 3'-kinase in a death domain-dependent manner. In contrast, FADD-null cells show hyperactivation of these kinases. Examining physical associations of endogenous proteins, we show that FADD interacts with interleukin-1 receptor-associated kinase 1 (IRAK1) and MyD88. LPS stimulation increases IRAK1-FADD interaction and recruitment of the IRAK1-FADD complex to activated MyD88. IRAK1 is required for FADD-MyD88 interaction, as FADD does not associate with MyD88 in IRAK1-null cells. By shuttling FADD to MyD88, IRAK1 provides a mechanism for controlled and limited activation of the TLR4 signaling pathway. Functionally, enforced FADD expression inhibited LPS- but not vascular endothelial growth factor-induced endothelial cell sprouting, while FADD deficiency led to enhanced production of proinflammatory cytokines induced by stimulation of TLR4 and TLR2, but not TLR3. Reconstitution of FADD reversed the enhanced production of proinflammatory cytokines. Thus, FADD is a physiological negative regulator of IRAK1/MyD88-dependent responses in innate immune signaling.

* Corresponding author. Mailing address: Department of Medical Biophysics, British Columbia Cancer Research Centre, 675 West 10th Ave., Vancouver, BC V5Z 1L3, Canada. Phone: (604) 675-8033. Fax: (604) 675-8049. E-mail: akarsan{at}bccrc.ca

{triangledown} Published ahead of print on 4 September 2007.

Molecular and Cellular Biology, November 2007, p. 7394-7404, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00600-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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