TRAF3: a novel tumor suppressor gene in macrophages

Abstract

Tumor necrosis factor receptor-associated factor 3 (TRAF3), a member of the TRAF family of cytoplasmic adaptor proteins with E3 ligase activity, is ubiquitously expressed in various cell types of the immune system. It is shared for signaling by a variety of adaptive and innate immune receptors as well as cytokine receptors. Previous studies examining conditional TRAF3-deficient mouse models that have the Traf3 gene specifically deleted in B lymphocytes or T lymphocytes have revealed the diverse and critical in vivo functions of TRAF3 in adaptive immunity. Although in vitro evidence points to a pivotal and indispensable role for TRAF3 in type I interferon production induced by pattern recognition receptors in macrophages and dendritic cells, the in vivo functions of TRAF3 in the innate immune system had long remained unclear. Three laboratories have recently addressed this gap in knowledge by investigating myeloid cell-specific TRAF3-deficient (genotype: TRAF3flox/floxLysM+/Cre) mice. The new evidence together demonstrates that specific ablation of TRAF3 in myeloid cells leads to inflammatory diseases, altered progression of diabetes, and spontaneous development of different types of tumors and infections in mice. These new findings indicate that TRAF3 acts as an anti-inflammatory factor and is required for optimal innate immunity in myeloid cells. Strikingly, the new evidence also identifies TRAF3 as a novel tumor suppressor gene in macrophages and other myeloid cells. In this review, we discuss and summarize the new findings and current knowledge about the multi-faceted regulatory roles and complex signaling mechanisms of myeloid cell TRAF3 in inflammation, innate immunity, and tumor development.

Molecular profiling of nonalcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis

“…On the other hand, Traf3 is a member of the TNF receptor-associated factor protein family, and is a positive regulator of type I IFN signaling and a negative regulator of alternative nuclear factor κB signaling ( 43 ). Traf3 has been reported to function as a tumor suppressor in nasopharyngeal carcinoma as well as in macrophages and myeloid cells ( 44 ). Interestingly, Li and coworkers ( 45 ) also recently reported that Traf3 promotes liver steatosis, suggesting the potential link between Traf3 and NAFLD-HCC.…”

miR-455 inhibits neuronal cell death by targeting TRAF3 in cerebral ischemic stroke

“…TRAF3 serves in anti-inflammatory signaling, and its deletion in myeloid cells leads to inflammatory diseases and cancer in mice 30. Recently, Gong et al16 showed that neurons are the main target of TRAF3 in brain tissue, and TRAF3 contributes to c-Jun kinase-, nuclear factor κB-, and Rac-1-induced neuronal death via activation of transforming growth factor-β-activated kinase 1 (TAK1).…”

Genetic Alterations of TRAF Proteins in Human Cancers

“…Interestingly, specific deletion of TRAF3 from myeloid cells (granulocytes, monocytes, and macrophages) leads to spontaneous development of histiocytic sarcomas derived from TRAF3 −/− tissue-resident macrophages in aging mice ( 56 , 174 ). The pathogenic mechanisms are likely related to the enhanced TLR-induced inflammatory responses observed in TRAF3 −/− macrophages through constitutive activation of NF-κB2, c-Rel, and IRF5, as described for TRAF2 −/− macrophages ( 56 , 174 ). Two other mouse models with functional relevance to TRAF3, Dok1 −/− Dok2 −/− Dok3 −/− mice and humanized TLR7/TLR8 transgenic mice, also spontaneously develop histiocytic sarcomas ( 175 , 176 ).…”

“…For example, disorders of innate antibacterial response are of fundamental importance in the development of gastrointestinal cancers, including pancreatic cancer, and increased expression of TRAF6, TLR4, and NOD1 are detected in peripheral blood leukocytes of pancreatic cancer patients ( 337 ). Specific deletion of TRAF3 from myeloid cells leads to development of B lymphomas and liver cancer in mice ( 56 , 174 ). Similarly, lymphocyte-specific TRAF3 transgenic mice develop autoimmunity, inflammation and cancers (such as squamous cell carcinomas of the tongue, salivary gland tumors, and hepatoma) ( 55 ).…”