Inflammation and cancer cell survival: TRAF2 as a key player

Abstract

TNF receptor-associated factor 2 (TRAF2) plays a crucial role in both physiological and pathological processes. It takes part in the regulation of cell survival and death, tissue regeneration, development, endoplasmic reticulum stress response, autophagy, homeostasis of the epithelial barrier and regulation of adaptive and innate immunity. Initially identified for its interaction with TNF receptor 2 (TNFR2), TRAF2 contains a TRAF domain that enables homo- and hetero-oligomerization, allowing it to interact with multiple receptors and signaling molecules. While best known for mediating TNFR1 and TNFR2 signaling, TRAF2 also modulates other receptor pathways, including MAPK, NF-κB, and Wnt/β-catenin cascades. By regulating NF-κB-inducing kinase (NIK), TRAF2 is a key activator of the alternative NF-κB pathway, linking it to inflammatory diseases, immune dysfunction, and tumorigenesis. In the innate immune system, TRAF2 influences macrophage differentiation, activation, and survival and stimulates natural killer cell cytotoxicity. In the adaptive immune system, it represses effector B- and T-cell activity while sustaining regulatory T-cell function, thus promoting immune suppression. The lack of fine-tuning of TRAF2 activity leads to excessive NF-kB activation, driving chronic inflammation and autoimmunity. Although TRAF2 can act as a tumor suppressor, it is predominantly described as a tumor promoter, as its expression has been correlated with increased metastatic potential and poorer prognosis in several types of cancer. Targeting TRAF2 or TRAF2-dependent signaling pathways might represent a promising anti-cancer therapeutic strategy.

Fig. 1. Structure-to-function relationship of TRAF2.

A Self-oligomerization of TRAF2 (upper panel) and heterotrimer (TRAF2:TRAF1) formation (lower panel). The (partial) available structures of monomeric TRAF2 domains are represented in different colors: purple and cyan = RING domain + first zinc finger motif (PDB file: 3knv); green = TRAF-N (PDB: 3m06); red = TRAF-C (PDB: 1ca4). B The structure of selected partners of TRAF2 is shown (extracted from the following PDB files: receptor, 1tnr; TRADD, 1f3v; cIAPs, 3m0a). TRAF2 partners are correlated to the corresponding interacting regions of TRAF2 (red, green and purple arrows). At the bottom, the position of the four TRAF2 domains in the sequence is represented in the corresponding colors. The union of the TRAF-N and TRAF-C is referred to as the “TRAF domain,” following the traditional nomenclature reported in the literature.

Fig. 2. TRAF2 role in the TNFR1 and TNFR2 signaling pathways.

TNFR1 is activated either by mTNF-α or sTNF-α and recruits TRADD, RIPK1, TRAF2 and cIAP1/2, forming Complex I. cIAP1/2 ubiquitinates RIPK1 creating a platform for the recruitment of TAB2/3 and TAK1 which, in turn, activate JNK, AP-1 and p38 resulting in cell survival and activates NIK, which triggers NF-kB activation promoting inflammation. When RIPK1 is deubiquitinated, cell death is triggered either through apoptosis, which is activated by the formation of the FADD/pro-caspase 8 complex, or through necroptosis, which is induced by the interaction between RIPK1 and RIPK3. TNFR2 is activated by mTNF-α and recruits TRAF2 and cIAP1/2 and, in this way, activates the noncanonical NF-kB pathway and cell proliferation. TNFR2 also activates Etk/Bmx, which, by forming a complex with VEGFR2, activates the PI3K/Akt/STAT5 axis.

Fig. 3. TRAF2 role in the canonical and noncanonical Wnt signaling pathways.

A In the canonical pathway, Wnt activates its receptor, FZD, and results in the recruitment of the scaffold protein, DVL, and to the cytoplasmic accumulation of β-catenin. TRAF2 participates in the TNIK-dependent activation of TCF-4/LEF, which forms a complex with β-catenin and activates the transcription of Wnt target genes involved in cytoskeletal organization and wound healing. B The noncanonical pathway is triggered by the interaction of Wnt5a to FZD5 and ROR1, which promotes the formation of the TRAF2/RIPK1 complex and results in the activation of NF-kB and the promotion of inflammation.

Fig. 4. TRAF2 roles in ER stress response and epithelial barrier homeostasis.

A TRAF2 interacts with the cytoplasmic portion of IRE1 and promotes the activation of JNK and NF-kB, thus inducing an inflammatory response. Conversely, TRAF2 induces the activation of caspase 12 and the apoptotic process. B Downstream of TNFR1, USP48 promotes the stabilization of TRAF2, leading to the activation of JNK and downregulation of E-cadherin. In this way, TRAF2 contributes to the decreased epithelial barrier.

Fig. 5. TRAF2 roles in cancer.

A TRAF2 forms a complex downstream of TNFR1 with RIPK1, TRADD, and cIAP1/2, which inhibits apoptosis and activates NF-kB, JNK and p38. NF-kB, in turn, increases the expression of VEGF, thus sustaining angiogenesis. Also, both VEGF and NF-kB promote the differentiation of Tregs, thus sustaining immune escape. VEGF contributes to immune suppression by stimulating the proliferation of MDSCs. p38 and JNK promotes cell survival, and, in addition, JNK sustains EMT and, therefore, cancer aggressiveness. By promoting NIK degradation, the TRAF2-mediated TNFR1 signaling seems to play a role in the polarization of macrophages towards an M2 pro-tumoral phenotype. B TRAF2 stimulates cancer aggressiveness by activating the PI3K/Akt/mTOR signaling pathway downstream of TNFR2. This pathway inhibits autophagy and, by suppressing TRAF2 degradation, promotes the M2 macrophage polarization. C TRAF2 sustains the noncanonical Wnt signaling mediated by Wnt5a, which activates NF-kB and triggers inflammation. The dotted squares indicate the molecules or cellular events activated by each of the three receptors (purple dotted squares: TNFR1 pathway; green dotted squares: TNFR2 pathway; red dotted squares: Wnt5a pathway). DVL Disheveled, EMT epithelial–mesenchymal transition, FZD Frizzled.

Fig. 6. TRAF2-C surface structural features.

A Schematic representation of trimeric TRAF2-C (top view) cartoon (PDB file 1ca4) with the three subunits in different colors (blue, green and orange). The surface residues involved in the interaction with TRADD or with CD40 receptor peptide are shown in cyan and in purple, respectively (obtained from PDB files 1f3v and 1qsc). B Details of the TRADD and/or CD40 binding residual surface (side view) obtained from panel (A) upon a rotation of 90°.