Control of canonical NF-κB activation through the NIK–IKK complex pathway

作者：Brian J. Zarnegar, Soh Yamazaki, Jeannie Q. He, Genhong Cheng · 发表于：Proceedings of the National Academy of Sciences · 年份：2008 · DOI：10.1073/pnas.0707959105 · 被引用次数：187 · 研究领域：NF-κB Signaling Pathways、Immune Response and Inflammation、interferon and immune responses

Articles in recent years have described two separate and distinct NF-kappaB activation pathways that result in the differential activation of p50- or p52-containing NF-kappaB complexes. Studies examining tumor-necrosis factor receptor-associated factors (TRAFs) have identified positive roles for TRAF2, TRAF5, and TRAF6, but not TRAF3, in canonical (p50-dependent) NF-kappaB activation. Conversely, it recently was reported that TRAF3 functions as an essential negative regulator of the noncanonical (p52-dependent) NF-kappaB pathway. In this article, we provide evidence that TRAF3 potently suppresses canonical NF-kappaB activation and gene expression in vitro and in vivo. We also demonstrate that deregulation of the canonical NF-kappaB pathway in TRAF3-deficient cells results from accumulation of NF-kappaB-inducing kinase (NIK), the essential kinase mediating noncanonical NF-kappaB activation. Thus, our data demonstrate that inhibition of TRAF3 results in coordinated activation of both NF-kappaB activation pathways.