The Evolving Role of TRAFs in Mediating Inflammatory Responses

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.

Post-Transcriptional Inflammatory Response to Intracellular Bacterial c-di-AMP

“…Elements upstream of p38 in c-di-AMP-triggered signaling module are still unknown. However, intracellular receptors of other PAMPs such as RIG-I or NOD1 are capable of activating p38 (28,(30)(31)(32). Also, recent reports indicate that the cyclic dinucleotides from pathogens can directly bind to the oxidoreductase RECON and modulate the inflammatory response (43).…”

“…Alternative models of activation of p38 have been reported, including intracellular activation. Molecules that can be recognized by cytoplasmic pattern recognition receptors such as RIG-I or NOD1 were shown to activate p38 (28)(29)(30)(31)(32).…”

TNF-Receptor-Associated Factor 3 in Litopenaeus vannamei Restricts White Spot Syndrome Virus Infection Through the IRF-Vago Antiviral Pathway

“…In this study, we identified a TRAF3 homolog from L. vannamei (LvTRAF3) for the first time, explored its antiviral function and the relationship involving related immune pathways in shrimp. In mammals, TRAFs 1 through 6 share a conserved TRAF-C terminus, which is required for the hetero-and homo-oligomerization of TRAF proteins, and recruitment to TRAF binding motifs in the cytoplasmic domains of cell surface receptors, as well as certain cytoplasmic and nuclear proteins (1). LvTRAF3 also has a TRAF-C domain at its C terminus.…”

“…Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) are intracellular signal transducers for a number of members of the immune receptor superfamily, which converge on inducing the production of proinflammatory factors, interferons (IFNs) and/or antimicrobial peptides (AMPs) (1). A total of six TRAF families, TRAF1-6, have been identified in mammals, most of which are implicated with several innate immune responses (1).…”

Roles of TRAFs in Ischemia-Reperfusion Injury

“…Specially, since TRAFs were discovered in TNF-R signaling, its role has been expanded to include involvement in more and more other inflammatory cytokine receptors, such as receptors for IL-2, IL-6, IL-1β, IL-17, IL-18, IL-33, type I IFNs, type III IFNs, M-CSF, GM-CSF, and C-type lectin receptors (Dhillon et al, 2019;Swaidani et al, 2019). Certainly, as intracellular scaffolding molecules, TRAFs play an indispensable role via the complex interactions with the inflammatory cytokine receptors in regulating pathophysiological processes in many human diseases, including autoimmune diseases, cancers, atherosclerosis, and type II diabetes, and they even have been recommended as suitable targets for therapeutic intervention (Choi et al, 2018;Nagashima et al, 2018;Zhu et al, 2018;Dhillon et al, 2019;Sajjad et al, 2019;Sangare et al, 2019). Meanwhile, the biological and functional roles of TRAFs in ischemia-reperfusion injury (IRI) of various organs have received much attention in recent years.…”