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Review
.2018 Aug 9:9:1849.
doi: 10.3389/fimmu.2018.01849. eCollection 2018.

Tumor Necrosis Factor Receptor-Associated Factor Regulation of Nuclear Factor κB and Mitogen-Activated Protein Kinase Pathways

Affiliations
Review

Tumor Necrosis Factor Receptor-Associated Factor Regulation of Nuclear Factor κB and Mitogen-Activated Protein Kinase Pathways

Jian-Hong Shi et al. Front Immunol..

Abstract

Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) are a family of structurally related proteins that transduces signals from members of TNFR superfamily and various other immune receptors. Major downstream signaling events mediated by the TRAF molecules include activation of the transcription factor nuclear factor κB (NF-κB) and the mitogen-activated protein kinases (MAPKs). In addition, some TRAF family members, particularly TRAF2 and TRAF3, serve as negative regulators of specific signaling pathways, such as the noncanonical NF-κB and proinflammatory toll-like receptor pathways. Thus, TRAFs possess important and complex signaling functions in the immune system and play an important role in regulating immune and inflammatory responses. This review will focus on the role of TRAF proteins in the regulation of NF-κB and MAPK signaling pathways.

Keywords: inflammation; mitogen-activated protein kinases; nuclear factor κB; toll-like receptors; tumor necrosis factor receptor-associated factor; tumor necrosis factor receptors.

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Figure 1
Figure 1
The function and regulation of tumor necrosis factor receptor-associated factor (TRAF)6 in MyD88 signaling pathway. Upon stimulation with IL-1 or toll-like receptor (TLR) ligands, MyD88 recruits IL-1R-associated kinases (IRAKs) (including IRAK1, IRAK2, and IRAK4) and TRAF6 to assemble a MyD88 signaling complex. Once activated in the MyD88 complex, TRAF6 functions as an E3 ubiquitin ligase that catalyzes the synthesis of K63-linked polyubiquitin chains conjugated to itself or NF-κB essential modulator (NEMO) or existing as free ubiquitin chains. The self-ubiquitinated TRAF6 recruits the ubiquitin-dependent kinase transforming growth factor beta-activated kinase 1 (TAK1) and its downstream kinase IκB kinase (IKK) to assemble a signaling complex that facilitates TAK1 and IKK activation. This process requires the TAK1 regulatory subunit TAB 2 (or TAB 3) and the IKK regulatory subunit NEMO, both have ubiquitin-binding functions. Activated TAK1 mediates activation of IKK and mitogen-activated protein kinases (MAPKs), which further activate nuclear factor κB (NF-κB) (RelA- and c-Rel-containing complexes) and AP1. TRAF6 mediated NEMO ubiquitination also contributes to the activation of IKK and NF-κB. Several DUBs have been shown to negatively regulate TRAF6 function through deconjugation of its K63 polyubiquitin chains.
Figure 2
Figure 2
Tumor necrosis factor receptor-associated factor (TRAF)2 and TRAF5 in tumor necrosis factor receptor (TNFR)1 signaling. TNFα binding to TNFR1 triggers the assembly of a TNFR1-associated signaling complex, complex I, which is composed of TNF receptor-associated death domain (TRADD), receptor-interacting protein kinase 1 (RIP1), TRAF2 or TRAF5 (TRAF2/5), and the E3 ubiquitin ligases cIAP1 and cIAP2 (cIAPs). Upon activation, cIAPs conjugate K63-linked ubiquitin chains to RIP1, which facilitates recruitment and activation of the kinase transforming growth factor beta-activated kinase 1 (TAK1) as well as the recruitment of the linear ubiquitin ligase complex LUBAC. LUBAC conjugates linear ubiquitin chains to RIP1 and, thereby, facilitates the requirement of IκB kinase (IKK)via the linear ubiquitin-binding function of NF-κB essential modulator (NEMO). Subsequent ubiquitination of NEMO by LUBAC, along with TAK1-mediated IKKβ phosphorylation, results in IKK activation. The activated IKK and TAK1 mediate activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK)/AP1 signaling pathways that promote cell survival. TRAF2 also participates in the subsequent formation of a cytoplasmic complex, complex IIa, which mediates apoptosis induction. When caspase-8 is inhibited, TNFR1 signaling also leads to formation of complex IIb, leading to necroptosis. DUBs, including OTULIN and CYLD, negatively regulate signaling functions of LUBAC by cleaving linear ubiquitin chains. SPATA2, as a high-affinity binding partner of CYLD and LUBAC, facilitates CYLD function by recruiting CYLD to LUBAC.
Figure 3
Figure 3
Anti-inflammatory function of tumor necrosis factor receptor-associated factor (TRAF)2 and TRAF3 in toll-like receptor (TLR) signaling pathway. In responds to TLR stimulation, TRAF6 is recruited to the MyD88 signaling complex. Upon activation, the TRAF6 complex relocates from the plasma membrane to the cytoplasm, a signaling step required for activation of the downstream nuclear factor κB and mitogen-activated protein kinase (MAPK) pathways. TRAF3 negatively regulates TLR-stimulated proinflammatory cytokine inductionvia two potential mechanisms. The first is to target the MyD88–TRAF6 complex and prevents the relocation of TRAF6 to the cytoplasm, and the second is to function together TRAF2 and cIAPs to mediate ubiquitin-dependent degradation of two major proinflammatory transcription factors, c-Rel and interferon regulatory factor 5 (IRF5). TLR signaling temporarily overrides the negative signaling function of TRAF3 by inducing TRAF3 proteolysis. In this process, TRAF6 activates cIAPs (cIAP1 and cIAP2) through K63 ubiquitination, which in turn function as E3 ubiquitin ligases to mediate K48-linked ubiquitination and proteolysis of TRAF3. In microglia, Peli1 appears to cooperate with TRAF6 or function downstream of TRAF6 to mediate cIAP activation.
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