详细记录  
题名:Specificity of TRAF3 in its negative regulation of the noncanonical NF-kappa B pathway.
作者:He JQ, Saha SK, Kang JR, Zarnegar B, Cheng G.
来源:J Biol Chem[IF=5.854]. 2007 Feb 9;282(6):3688-94. Epub 2006 Dec 11.
URL :http://dx.doi.org/10.1074/jbc.M610271200
日期:070415
摘要: Jeannie Q. He1, Supriya K. Saha2, Jason R. Kang, Brian Zarnegar3, and Genhong Cheng?4

From the Department of Microbiology, Immunology, and Molecular Genetics, the Medical Scientist Training Program, and ?Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California 90095

Received for publication, November 3, 2006 , and in revised form, December 11, 2006.

ABSTRACT

Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are critical signaling adaptors downstream of many receptors in the TNF receptor and interleukin-1 receptor/Toll-like receptor superfamilies. Whereas TRAF2, 5, and 6 are activators of the canonical NF-B signaling pathway, TRAF3 is an inhibitor of the noncanonical NF-B pathway. The contribution of the different domains in TRAFs to their respective functions remains unclear. To elucidate the structural and functional specificities of TRAF3, we reconstituted TRAF3-deficient cells with a series of TRAF3 mutants and assessed their abilities to restore TRAF3-mediated inhibition of the noncanonical NF-B pathway as measured by NF-B-inducing kinase (NIK) protein levels and processing of p100 to p52. We found that a structurally intact RING finger domain of TRAF3 is required for inhibition of the noncanonical NF-B pathway. In addition, the three N-terminal domains, but not the C-terminal TRAF domain, of the highly homologous TRAF5 can functionally replace the corresponding domains of TRAF3 in suppression of the noncanonical NF-B pathway. This functional specificity correlates with the specific binding of TRAF3, but not TRAF5, to the previously reported TRAF3 binding motif in NIK. Our studies suggest that both the RING finger domain activity and the specific binding of the TRAF domain to NIK are two critical components of TRAF3 suppression of NIK protein levels and the processing of p100 to p52. 11:

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