Traf3, short for Tumor necrosis factor receptor (TNFR)-associated factor 3, is an adapter protein. It is involved in multiple signaling pathways, including those of the TNFR superfamily, Toll-like receptor (TLR) family, and retinoic acid-inducible gene I-(RIG-I)-like receptor (RLR) family. It can positively regulate type I interferon production while negatively regulating classical and nonclassical nuclear factor-κB, and mitogen-activated protein kinase (MAPK) signaling pathways [4]. Genetic models, such as KO and CKO mouse models, have been crucial in understanding its functions.

In macrophages, ablation of Traf3 increases M1 markers and down-regulates M2 markers, enhancing LPS-induced M1 and abolishing IL-4-induced macrophage polarization. Traf3 promotes STAT6 ubiquitination and transcriptional activity, and myeloid Traf3 deficiency suppresses tumor growth and lung metastasis in B16 melanoma mouse models, indicating its role in macrophage polarization and tumor progression [1]. In T lymphocytes, Traf3-deficient T cells from conditional knockout mice show abnormal proliferation, survival, cytokine production, and effector responses, suggesting its importance in T cell function [2]. In antiviral immunity, Nedd4l-mediated K29-linked cysteine ubiquitination of Traf3 positively regulates antiviral immunity, as Nedd4l deficiency impairs type I interferon and proinflammatory cytokine production in response to virus infection [3]. In cardiomyocytes, doxorubicin-induced upregulation of Traf3 promotes TAK1 autophosphorylation, leading to activated MAPKs pathway and cardiomyocyte apoptosis, and cardiomyocyte-specific Traf3-knockdown mice can potentially help understand doxorubicin-induced cardiotoxicity [5].

In conclusion, Traf3 is a multifaceted regulator in the immune system and other biological processes. Studies using KO/CKO mouse models have revealed its significance in macrophage polarization, T cell function, antiviral immunity, and the pathogenesis of doxorubicin-induced cardiomyopathy. These findings contribute to understanding the underlying mechanisms of related diseases and may provide potential therapeutic targets.