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Review
. 2016 Nov;1860(11 Pt B):2646-55.
doi: 10.1016/j.bbagen.2016.05.021. Epub 2016 May 18.

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

Emine Guven-Maiorov  1 , Ozlem Keskin  2 , Attila Gursoy  3 , Carter VanWaes  4 , Zhong Chen  5 , Chung-Jung Tsai  6 , Ruth Nussinov  7
Affiliations
Review

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

Emine Guven-Maiorov et al. Biochim Biophys Acta. 2016 Nov.

Abstract

Background: The tumor necrosis factor receptor (TNFR) associated factor 3 (TRAF3) is a key node in innate and adaptive immune signaling pathways. TRAF3 negatively regulates the activation of the canonical and non-canonical NF-κB pathways and is one of the key proteins in antiviral immunity.

Scope of review: Here we provide a structural overview of TRAF3 signaling in terms of its competitive binding and consequences to the cellular network. For completion, we also include molecular mimicry of TRAF3 physiological partners by some viral proteins.

Major conclusions: By out-competing host partners, viral proteins aim to subvert TRAF3 antiviral action. Mechanistically, dynamic, competitive binding by the organism's own proteins and same-site adaptive pathogen mimicry follow the same conformational selection principles.

General significance: 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.

Keywords: Antiviral immunity; Cancer; Evolvable; Host-pathogen interactions; Inflammation; Structure.

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Figures

Fig. 1
Fig. 1
TRAF3 is a hub protein at the crossroad of immune system receptors and several viral proteins that turn its signaling on or off. TRAF3 regulates the activation of canonical and non-canonical NF-κB and the generation of anti-viral responses. Since TRAF3 controls signaling through several pathways, it is targeted by many viral proteins. Rectangular shapes correspond to cellular proteins and diamond shapes are viral proteins. Black lines show interactions through host proteins and the red lines show interactions with viral proteins.
Fig. 2
Fig. 2
Canonical and non-canonical NF-κB pathways. TLRs and TNFRs activate the (a) classical NF-κB signaling, whereas only some subtypes of TNFRs, such as CD40, BAFFR activate (b) the alternative NF-κB. NF-κB has different subunits: RelA (p65), p50, RelB, and p52. They form heterodimers and translocate to the nucleus to initiate transcription when IKK phosphorylates and inactivates IκB (inhibitor of NF-κB). The distinct combinations of subunits trigger the transcription of different effector genes.
Fig. 3
Fig. 3
Domain structure of TRAF3. TRAF3 has two domains: (a) a TRAF domain at its C terminus – consisting of β-sandwich TRAF-C and coiled coil TRAF-N –, and (b) a RING domain at its N terminus.
Fig. 4
Fig. 4
Interactions of TRAF3 through its TRAF-C region. TRAF3 interacts with many proteins through its TRAF-C region. Since the surface on this region is limited, TRAF3 uses same or overlapping surface patches (interfaces) to interact with different partners. Some of the interactions shown here have already resolved structures (LTβR , CD40 , BAFFR , LMP1 , MAVS , and TANK [34]). We modeled the rest. The dashed rectangles show the interfaces on TRAF3 and the solid lines show which interactions share these interfaces. Since the two dashed rectangles overlap, all interactions shown in this figure have overlapping interfaces with all other interactions. Thus, all are potentially competitive.
Fig. 5
Fig. 5
Distinct cellular outcomes are observed when TRAF3 interacts with NIK and TNFRs. Our structural model supports the experimental finding of NIK's displacement upon receptor binding and explains why NIK is not degraded in stimulated cells. Some TNFRs form trimers upon stimulation, but others preassemble into trimers before stimulation . They recruit trimeric TRAFs. TRAFs trimerize through their TRAF-C region and dimerize through their RING domain , . (a) In the unstimulated cell, NIK is bound to TRAF3-TRAF2 heterotimer, gets ubiquitinated by cIAPs, and gets degraded. The structure of TRAF2-cIAP complex is available (PDB ID: 3M0A). We obtained the heterotrimer of TRAF3 and TRAF2 by superimposing TRAF2 onto TRAF3 unit cell trimer. TRAF3-NIK interaction is modeled by PRISM , , . (b) When TNFRs recognize their ligands they recruit TRAF3 homotrimers to their cytoplasmic domain. Since TNFRs and NIK bind to the same site on TRAF3, TNFR-TRAF3 interaction liberates NIK and prevents its ubiquitination. NIK accumulates and activates non-canonical NF-κB. Here, the structure of TRAF3-LTβR (PDB ID: 1RF3) is shown as an example of TNFR activation.
Fig. 6
Fig. 6
Structural details of TRAF3 interactions revealed how TRAF3 inhibits both the canonical and non-canonical NF-κB pathways. Structural details of TRAF3 interactions corrected critical misinterpretation and unravel what may happen in actual scenario. In TLR signaling, it was assumed that TRAF3 inhibits directly TRAF6, but structural data show that it inhibits the MyD88-TRAF6 interaction and hence prevents activation of the canonical NF-κB pathway. In TNFR signaling, the presumption was that TRAF3 blocks NIK; however structural data suggest that TRAF3-TNFR interaction prevents TRAF3-NIK association. Black lines show what was assumed before and red lines show what is revealed by the structural details of our models.
Fig. 7
Fig. 7
TRADD binds to TRAF2 and TRAF3 in a similar fashion. (a) While TRAF2-TRADD complex structure is available on PDB (PDB ID: 1F3V) , (b) we modeled TRAF3-TRADD by PRISM , , . Our structural model for TRADD-TRAF3 is very similar to TRADD-TRAF2 crystal structure.
Fig. 8
Fig. 8
Modeled TRAF3 interactions through its RING domain. PRISM , , predicted TRAF3 interactions with OTUB1 and SRC through its RING domain. These interactions have fully or partially overlapping interfaces, therefore they cannot co-exist. OTUB1 is a negative regulator of TRAF3-dependent IFN production . However, SRC promotes TRAF3-dependent IFN production since its siRNA leads to decreased IFN production . Competitive displacement of OTUB1 from TRAF3 may be the underlying cause for the increased IFN production in SRC recruitment to TRAF3, since TRAF3 signaling is not restricted to one negative regulator.
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