TRAF3 signaling: Competitive binding and evolvability of adaptive viral molecular mimicry

Abstract

Our premise is that irrespective of the eliciting event - physiological or acquired pathogenic trait - pathway activation (or suppression) may embrace similar conformational principles. However, even though here we largely focus on competitive binding at a shared site, similar to physiological signaling other pathogen subversion mechanisms can also be at play. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang.

Pathogen mimicry of host protein-protein interfaces modulates immunity

“…Above we provided several examples. Our recent work on TRAF3, a key protein in antiviral immunity which negatively regulates the activation of the canonical and noncanonical NF-κB pathways, provides another example [72]. Viral proteins, such as LMP1 of EBV [50] and vFLIP (viral FADD-like interleukin-1-b-converting enzyme (FLICE)/caspase-8-inhibitory protein) of Kaposi's sarcoma herpesvirus [73], that mimic the conformation of the surface of TRAF3's physiological partners compete with TRAF3's host-encoded partners, and constitutively activate NF-κB in a ligand-independent manner.…”

TRAF3 enhances STING-mediated antiviral signaling during the innate immune activation of black carp

“…In 1994, similar to the method of discovering TRAF1 and TRAF2, a new protein with zinc fingers and a TRAF domain was discovered through yeast two-hybrid screening and this protein could interact with CD40 and help transduce downstream signaling, which was named as TRAF3 later (Hu et al, 1994). Notably, TRAF3 is a master regulator at the crossroads of antiviral and anti-inflammatory pathways; its deletion in myeloid cells leads to inflammatory diseases and cancer in mice (Guven-Maiorov et al, 2016). Black carp contributes importantly to the fresh water industry of China; however, its innate immune system remains much unknown.…”

“…Like other TRAF family members, TRAF3 exhibits a modular structure with well-defined functional domains, including a conserved TRAF domain, several Zinc finger (ZF) motifs and a RING domain (Häcker et al, 2011). Normally, TRAF3 functions as K63-specific ubiquitin ligases, which alter the function of target proteins through their non-degradative, site-specific ubiquitination activity and activate T several downstream proteins (Guven-Maiorov et al, 2016). Notably, the C-terminal TRAF domain (also known as MATH domain) and the Nterminal RING domain play the critical role in TRAF3 functioning (Häcker et al, 2011;Ni et al, 2002).…”

Intracellular and intercellular signaling networks in cancer initiation, development and precision anti-cancer therapy

“…Disruption of the gut microbiota impairs the efficiency of immuno- and chemotherapies [56]. In the closing contribution of this special issue Ruth Nussinov and co-workers [57–59] explore a highly exciting special area of cell-cell interactions: the mimicry of host protein binding surfaces by pathogenic proteins. This mimicry leads to the rewiring and repurposing of the host signaling pathways contributing to carcinogenesis including the modulation of RAS-signaling.…”