A TRIP Back in Time to TRIP

Abstract

TRAF-interacting protein (TRIP, TRAIP and RNF206) was initially known as a binding partner that prevented NF-kβ activation. Currently, it is defined as a protein encoded as TRIP gene in humans. TRIP gene encodes an amino acid that has N-terminal RING finger motif. The same murine protein associates with TNFR-linked factor 1 also known as TRAF 1. It also interacts with TRAF 2 and cylindromatosis. The association with TRAF 2 leads to cell activation such as NF-κB activation. Tumor Necrosis factor receptor (TNFR) associated factors are primary adapter molecules in the TNF-signaling pathway and induce a wide range of biological processes including cell proliferation, activation, differentiation, and apoptosis. TRIP can also be defined as a novel binding protein that detrimentally influences and regulates the NF-KB activation via the TNFR2and CD30 signaling complexes. Nonetheless, studies show that TRIP being part of several processes such as DNA stability and cell cycle progression by direct association with other binding partners is not evidence enough for its integral role. Irrespective of TRIP, being an influencing factor in cell signaling and human diseases, the physiological importance and the exact role of TRIP is not clear. As such, the review seeks to demystify, and explain the role of TRIP in various signaling pathway based on recent published research. induce a wide range of biological processes including cell proliferation, activation, differentiation, and apoptosis. TRAF members directly interact with the TNFR super-family via their cytoplasmic domains [1]. Cytoplasmic domains of TNFR lack catalytic activity and possess no significant homology to each other or other known proteins [2]. To date, TRAF1-7 has been identified. Except for TRAF7, other TRAF members possess a conserved TRAF domain which is composed of (~230 amino acid length) TRAF-N and TRAF-C domain which plays a pivotal role in TRAF signaling complexes by interacting directly via cytoplasmic regions of TNFR superfamily. It is now clear that TRAF-N domain mediates the interaction with different intracellular signaling molecules. TNFR super-family members recruit several types of signal transducer molecules which have been identified to initiates different signaling pathways. Moreover, one class of signalTransducing molecules are recruited to Fas (CD90) or TNFR1 via their death domain. For example, through their respective Death domain interactions, Fas (CD95) and TNFR1 recruit FADD (MORT1)/RIP or TRADD/FADD/RIP. Association of these signal transducers lead to the recruitment of FLICE/MACH and finally causes cell death [3]. Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) are second class of signal transducers, recruited by TNFR superfamily via their cytoplasmic interactions and either activates or suppresses the NF-Kb or JNK pathway. The ability of TRAF’s to bind TNFR2, CD30, CD40, and LT-BR has been identified by their biochemical studies. The interaction of these receptors with TRAFs occur directly via a short stretch of amino acids within cytoplasmic tails, but don’t interact Citation: Bhat EA, Rather IA (2018) “A TRIP Back in Time to TRIP”. J Proteomics Bioinform 11: 138-142. doi: 10.4172/0974-276X.1000480 Volume 11(8) 138-142 (2018) 139 J Proteomics Bioinform, an open access journal ISSN: 0974-276X with proteins contains Death domains [4]. TRAF-interaction Protein (TRIP) a signaling molecule directly associated with TRAF1 and TRAF2 proteins leads to downstream inhibition of NF-kB inhibition. TRIP is composed of 469 amino-acids with annotated domains including an N-terminal E3 Ubiquitin ligase activity Ring Finger motif followed by Coiled-coil and Leucine Zipper domain that is engaged in the TRAF-mediated signaling [5]. Initially, TRIP has been recognized as TNF interacting protein by Yeast Two-hybrid assay, directly interacts with the TRAF1 and TRAF2 proteins, which leads to the inhibition of NF-kB activation. TRIP has emerged a novel binding protein which negatively regulates the NF-KB activation through the TNFR2and CD30 signaling complexes. TRIP plays multifunctional roles in antiviral response, cell proliferation, and apoptosis. However, recently, it has been shown that TRIP is more related to DNA stability, cell cycle progression by direct interaction with other binding partners. The critical role of TRIP in Cell cycle progression, DNA repair pathways, DNA damage response and embryonic development, have increased our interest in exploring how TRIP interact with different binding partners. Despite being involved in cell signaling and human diseases, the physiological significance and precise role of TRIP have not been yet clearly known. TRIP is a member of RINGtype E3 Ubiquitin ligase family that undergoes autoubiquitination, but no studies have shown clearly its physiological functions and its substrates like NOPO a Drosophila homolog of human gene encoding TRIP till now. The E3 ring domain is followed by the Coiled-Coil and Leucine zipper domain which is critical for the protein-protein interaction. Different studies were carried to find out which domain of the protein is critical for the protein-protein interaction. However more need to be done about this protein signaling complexes. Moreover, the response shown by N-terminal RING domain of TRIP for degradation of TBK1 is mediated by ubiquitination and has been shown to be involved in TLR3/4and RIG-I–mediated IFN-β signaling and antiviral responses [4]. Role of TRIP in Different Signaling Processes TRIP in TRAF signaling pathway Initially, TRIP has been reported as the binding partner of TRAF1 and TRAF2 in a Two-Hybrid screen, suppresses the NF-ƙB activation by directly binds to the TRAF1 and TRAF2 without an unseen mechanism. Members of the tumor necrosis factor (TNF) family elicit a diverse range of biological responses including cellular proliferation, differentiation, and apoptosis. The tumor necrosis receptor (TNFR) and toll-like receptor (TLR) family are signaling pathways in which TRAF proteins play important roles in the immune system and acts as a key adaptor signaling molecules which govern downstream signal. To date, TRAF1-7 has been identified in mammals. Various studies have been shown that TRIPCC is important for the interaction of CC domain of TRAF1 and TRAF2 and have shown negatively regulates the activation of NF-Kβ as shown in Figure 1. This inhibition is independent of the E3 Ubiquitin ligase activity and occurs probably by interference with receptor recruitment of TRAF proteins [6]. The Lung cancer development is associated with the TRAF family members, specifically TRAF6 promoted the cell death of lung cancer cells [7]. Moreover, TRAF2 through the interaction with TRAF interacting protein with a forkhead associated (FHA) domain (TIFA) associated with a signal transduction leads the lung cancer development [8-10]. TRIP in RAP80 signaling pathway Receptor-associated protein 80 (RAP80) is one of the elements in BRCA1-A complex [11]. Its role is to recruit BRCA1 to DNA lesion locus in deoxy-ribonucleic acid in ubiquitin signaling pathway. It is needed for BRCA1 and BRCC36 localization of DSBs [12]. According to Lee et al., TRIP acts as a novel binding agent of RAP80 through a yeast two-hybrid system. The results of the study revealed that TRAIP is one of the upstream controllers for RAP80. As such, it plays a critical role in the conscription of RAP80 to deoxy-ribonucleic acid lesions in a proper way. This happens with the presence of an identified K-63lined polyubiquitin appreciation at the locus of deoxy-ribonucleic acid damage. When there is no damage to the DNA, both TRIP and RAP80 are retained. The retention of both happens in PML nuclear bodies. However, when there is DNA damage, TRIP might translocate RAP80 to where the damage has occurred. It does so through the guidance of RNF20–RNF40 complex which is integral in H2B ubiquitination at the locus of DNA damage. Because of this, TRIP ends up conscripting BRCA1 complex next to the locus DNA damage occurred [13]. It does this by interrelating with RAP80 allowing DNA lesion checkpoint and the HR repair. The lack of RNF8/168 regulation by deleting TRIP lead to the localization of 53BP1. Nonetheless, when TRIP is not present, then the translocation of RAP80 takes place. Hence, the downstream