Oncogenic Role of Tumor Necrosis Factor α-Induced Protein 8 (TNFAIP8)

Abstract

Tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8) is a founding member of the TIPE family, which also includes TNFAIP8-like 1 (TIPE1), TNFAIP8-like 2 (TIPE2), and TNFAIP8-like 3 (TIPE3) proteins. Expression of TNFAIP8 is strongly associated with the development of various cancers including cancer of the prostate, liver, lung, breast, colon, esophagus, ovary, cervix, pancreas, and others. In human cancers, TNFAIP8 promotes cell proliferation, invasion, metastasis, drug resistance, autophagy, and tumorigenesis by inhibition of cell apoptosis. In order to better understand the molecular aspects, biological functions, and potential roles of TNFAIP8 in carcinogenesis, in this review, we focused on the expression, regulation, structural aspects, modifications/interactions, and oncogenic role of TNFAIP8 proteins in human cancers.

Keywords: autophagy; cell survival; oncogene; tumor necrosis factor α (TNFα); tumor necrosis factor α-inducing protein 8 (TNFAIP8).

Figure 1

(A) Amino acid similarity and identity of TIPE family members, TIPE1, TIPE2, TIPE3, and mTNFAIP8, with humanTNFAIP8 (hTNFAIP8) isoform 2 are presented. The percentage of amino acid similarity and identity was determined by Emboss needle (http://www.ebi.ac.uk/Tools/psa/emboss_needle/ accessed on: 10 October 2018). (B) Amino acid sequence alignments of TIPE family members such as hTNFAIP8, mTNFAIP8, TIPE1, TIPE2, and TIPE3 were performed by using EMBL-EBI Clustal Omega software tools (https://www.ebi.ac.uk/Tools/msa/clustalo/, accessed on: 5 October 2018).

Figure 2

(A) Amino acid sequences of human TNFAIP8 (hTNFAIP8) protein isoforms are presented. The variable N-terminal region is shown in different colors. (B) Amino acid sequence alignments of hTNFAIP8 protein isoforms. The highly conserved coiled-coil structural motif and D-Box (destruction box) consensus are shown. (https://www.ebi.ac.uk/Tools/msa/clustalo/, accessed on: 5 October 2018). (C) Location of the coiled-coil domain and D-Box consensus on TNFAIP8 isoform 2 are presented. D-Box amino acid consensus of TNFAIP8 and other known D-Box motif-containing proteins are listed.

Figure 3

(A) The major seven α helices of human TNFAIP8 isoform 2 are presented in different colors and location of the coiled-coil domain and D-Box motif in helices are shown. (B) Rendering of the homology model of hTNFAIP8 isoform 2. Left panel: Colored ribbon diagram and molecular surface of the binding pocket, with pink representing the hydrophilic region and green the hydrophobic region. Middle Panel: Ribbon diagram with molecular surface of the binding pocket and the bound ligand (PE). Right Panel: Conserved pocket residues interacting with the ligand (PE). Human TNFAIP8-Tyr-76 and mouse TNFAIP8-His-86 form hydrogen bonds with the PE phosphate group, respectively. The molecular modeling software used for the graphic visualization was the Molecular Operating Environment (MOE 2016, Chemical Computing Group, Toronto, ON, Canada). The binding site surface was generated as molecular surface based on the alpha spheres generated in MOE. By MOE convention, pink color indicates hydrophilic surface region and green indicates hydrophobic region. PE—phosphatidylethanolamine. CC Domain—coiled-coil domain. CHC—central hydrophobic cavity.

Figure 4

(A,B) Prediction of phosphorylation sites of TNFAIP8 were performed by using NetPhos server 3.1 (http://www.cbs.dtu.dk/services/NetPhos/, accessed on: 15 July 2018) and Prosite search (https://prosite.expasy.org/, accessed on: 10 July 2018) (B) Locations of predicted pSer and pThe phosphorylation sites of TNFAIP8 isoform 2 are presented (upper schematic). Phosphorylation sites, associated kinases, and NetPhos scores are presented (lower table). Both NetPhos and Pro-site server-predicted phosphorylation sites and kinases are shown in red color (lower table). pSer—phospho-Serine. pThe—phospho-threonine.

Figure 5

(A) The biological roles of TIPE family proteins in cell survival and cell death are suggested. (B) The schematic model represents the involvement of TNFAIP8 in the regulation of different cellular processes in cancer cells.