TRAF‐Mediated TNFR‐Family Signaling

Abstract

The tumor necrosis factor (TNF) superfamily consists of a wide variety of cell-bound and secreted proteins that regulate numerous cellular processes. In particular, TNF-family proteins regulate the proliferation and death of tumor cells, as well as activated immune cells. This overview discusses the mammalian TNF receptor-associated factors (TRAFs), of which TRAF1, 2, 3, 5, and 6 have been shown to interact directly or indirectly with members of the TNF receptor superfamily. Structural features of TRAF proteins are described along with a discussion of TRAF-interacting proteins and the signaling pathways activated by the TRAF proteins. Finally, we examine the phenotypes observed in TRAF-knockout mice.

Opposing Roles for TRAF1 in the Alternative versus Classical NF-κB Pathway in T Cells

“…However, they differ in their N-terminal domains. TRAF2-6 contain a series of zinc finger domains and a RING finger domain that can potentially function as an E3 ubiquitin ligase to affect downstream signaling pathways (10). In contrast, TRAF1 differs from the other TRAF family members in lacking a RING finger domain and containing only one zinc finger, thus resembling a dominant negative form of TRAF2 (11).…”

TNF Receptor-Associated Factor (TRAF) Signaling Network in CD4⁺ T-Lymphocytes

“…Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) are intracellular signaling proteins that were initially identified as molecules interacting with various members of the TNFR superfamily and that mediate the link between receptor-proximal activation events and intracellular signaling proteins. Six TRAF family proteins, which share a conserved C-terminal TRAF-C domain, have been identified (Inoue et al 2000;Chung et al 2002;Ha et al 2009) (Fig. 2).…”

“…The cytokine receptors that recruit TRAFs are receptors for IL-1, IL-2, . TRAFs also participate in the signal transduction by receptors, such as the Toll-like receptors (TLRs), the nucleotide binding-oligomerization domain (NOD)-like receptors (NLRs), and the retinoic acidinducible gene (RIG)-I-like receptors (RLRs) (Takeda et al 2003;Ha et al 2009;Kawai and Akira 2010;Hacker et al 2011). This review summarizes findings on the importance of TRAF-family proteins in regulating the three critical signals for the activation, differentiation, and survival of conventional CD4 + T cells and other T-cell subsets.…”

“…2), have an N-terminal really interesting new gene (RING)/zinc-finger domain that functions as an ubiquitin E3 ligase to promote the assembly of polyubiquitin chains on signaling proteins. This polyubiquitination is critical for activation of downstream signaling cascades, such as those mediated by the canonical and noncanonical nuclear factor κB (NF-κB) and by the mitogen-activated protein kinases (MAPKs), which include the extracellular signal-regulated protein kinase (ERK), c-Jun NH 2 -terminal kinase (JNK), and p38 (Chung et al 2002;Ha et al 2009;Karin and Gallagher 2009;Hayden and Ghosh 2014).…”

“…TNFR-family molecules assemble signaling complexes that contain TRAF2, cIAP1, cIAP2, RIP1, IKKα/β/γ, and MAPK kinase kinases (MAP3Ks) such as MEK kinase 1 (MEKK1), TGF-β-activated kinase 1 (TAK1), and apoptosis signal-regulating kinase 1 (ASK1) and that promote the activation of canonical NF-κB and MAPK pathways (Takeda et al 2008;Ha et al 2009;Karin and Gallagher 2009;Silke and Brink 2010;So and Croft 2012;Varfolomeev et al 2012;Hayden and Ghosh 2014). For the canonical NF-κB pathway, activated IKKβ in the TNFR complex phosphorylates inhibitor of NF-κB (IκB), which leads to the Lys48 (K48)-linked ubiquitination and subse-quent proteasomal degradation of IκB.…”