Abstract
TRAFs [tumor necrosis factor (TNF) receptor associated factors] are a family of signaling molecules that function downstream of multiple receptor signaling pathways and play a pivotal role in the biology of innate, and adaptive immune cells. Following receptor ligation, TRAFs generally function as adapter proteins to mediate the activation of intracellular signaling cascades. With the exception of TRAF1 that lacks a Ring domain, TRAFs have an E3 ubiquitin ligase activity which also contributes to their ability to activate downstream signaling pathways. TRAF-mediated signaling pathways culminate in the activation of several transcription factors, including nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs; e.g., ERK-1 and ERK-2, JNK, and p38), and interferon-regulatory factors (IRF; e.g., IRF3 and IRF7). The biological role of TRAFs is largely due to their ability to positively or negatively regulate canonical and non-canonical NF-κB signaling. While TRAF-mediated signaling regulates various immune cell functions, this review is focused on the recent advances in our knowledge regarding the molecular mechanisms through which TRAF proteins regulate, positively and negatively, inflammatory signaling pathways, including Toll–IL-1 receptors, RIG-I like receptors, and Nod-like receptors. The review also offers a perspective on the unanswered questions that need to be addressed to fully understand how TRAFs regulate inflammation.
Highlights
The Tumor-Necrosis Factor (TNF) Receptor Associated Factor (TRAF) family is comprised of cytoplasmic adaptor proteins involved in transducing downstream effects of a variety of receptors [1]
In TRIF-mediated signaling, TRIF recruits TRAF3, which catalyzes its own K63-linked polyubiquitination. This leads to the activation of the TBK1 and the non-canonical IKK, IKKε, which in turn phosphorylates IRF3 resulting in its nuclear translocation and the subsequent induction of type 1 IFNs (IFN-Is) [22, 23]
MyD88 forms a complex with TRAF3 which recruits and activates an IL-1 receptor-associated kinase (IRAK)-IKKα complex, which in turn phosphorylates IRF7 resulting in its translocation into the nucleus to induce interferon production (Figure 1C) [9]
Summary
Bipandeep Dhillon 1†, Fatemah Aleithan 1†, Zahi Abdul-Sater 2 and Ali A. TRAFs [tumor necrosis factor (TNF) receptor associated factors] are a family of signaling molecules that function downstream of multiple receptor signaling pathways and play a pivotal role in the biology of innate, and adaptive immune cells. TRAF-mediated signaling pathways culminate in the activation of several transcription factors, including nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs; e.g., ERK-1 and ERK-2, JNK, and p38), and interferon-regulatory factors (IRF; e.g., IRF3 and IRF7). The biological role of TRAFs is largely due to their ability to positively or negatively regulate canonical and non-canonical NF-κB signaling. While TRAF-mediated signaling regulates various immune cell functions, this review is focused on the recent advances in our knowledge regarding the molecular mechanisms through which TRAF proteins regulate, positively and negatively, inflammatory signaling pathways, including Toll–IL-1 receptors, RIG-I like receptors, and Nod-like receptors. The review offers a perspective on the unanswered questions that need to be addressed to fully understand how TRAFs regulate inflammation
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