Specificity of TRAF3 in Its Negative Regulation of the Noncanonical NF-κB Pathway*

By Jeannie Q. He, S. Saha, Jason R Kang, B. Zarnegar, G. Cheng. Journal of Biological Chemistry, 2006

88 citations recorded by the source corpus.

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-κB signaling pathway, TRAF3 is an inhibitor of the noncanonical NF-κB 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-κB pathway as measured by NF-κB-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-κB 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-κB 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.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/ef36b95d215a66912a914d334aa9e8c37171be7f

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Citations in the corpus

Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. (2007, background): “Consistently, Traf3−/− mice are characterized by constitutive processing of NFKB2 (He et al., 2006a).”
Is NF-κB a good target for cancer therapy? Hopes and pitfalls (2009, background): “Normally, NIK is rapidly degraded in non-stimulated cells, and this degradation is required to keep NIK activity at a low basal leve”
Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-κB signaling (2008, result): “This activity was dependent on the N-terminal portion of TRAF2, which contains its RING finger; by contrast, deletion of the N-terminal RING finger of TRAF3 did not compromise its ability to induce NIK degradation, which is in contrast to a previous report that the RING finger of TRAF3 is essential ”