TRAF6, short for TNF receptor associated factor 6, is an E3 ubiquitin ligase. It is pivotal in NF-κB activation and autophagy activation, especially in pathways like TLR4 signaling [1]. It can also catalyze the synthesis and linkage of lysine-63 (K63) ubiquitin related to substrate protein stabilization [2]. TRAF6 is involved in numerous biological processes and is associated with various diseases, highlighting its overall biological importance. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In melanoma cells, suppression of TRAF6 expression down-regulates PD-L1 expression on the membrane surface, and TRAF6 enhances PD-L1 expression through YAP1-TFCP2 signaling [2]. In chronic inflammatory pain models, huc-MSCs-derived exosomes attenuate pain via the miR-146a-5p/TRAF6 axis, increasing autophagy and inhibiting pyroptosis [3]. In colorectal cancer, TRAF6 inhibits metastasis by regulating selective autophagic CTNNB1 degradation, but is phosphorylated and degraded by GSK3β in most clinical cases [4]. In breast cancer, inhibition of TRAF6 reduces cell migration, invasion, growth, tumour burden, and metastasis, and high TRAF6 expression is associated with poor survival [5]. In leukemia, loss of TRAF6 impairs leukemic function and induces metabolic alterations, indicating its oncogenic role [6].

In conclusion, TRAF6 plays essential roles in multiple biological processes, including immune responses, autophagy, and metabolic regulation. Through model-based research, especially KO/CKO mouse models if applicable, its role in diseases such as melanoma, chronic inflammatory pain, colorectal cancer, breast cancer, and leukemia has been revealed. These findings suggest that targeting TRAF6 could be a potential therapeutic strategy for these diseases.

References:

1. Min, Yoon, Kim, Mi-Jeong, Lee, Sena, Chun, Eunyoung, Lee, Ki-Young. 2018. Inhibition of TRAF6 ubiquitin-ligase activity by PRDX1 leads to inhibition of NFKB activation and autophagy activation. In Autophagy, 14, 1347-1358. doi:10.1080/15548627.2018.1474995. https://pubmed.ncbi.nlm.nih.gov/29929436/

2. Wang, Linglu, Liu, Xiaoyan, Han, Yuhang, Chen, Hongbo, Cheng, Fang. 2024. TRAF6 enhances PD-L1 expression through YAP1-TFCP2 signaling in melanoma. In Cancer letters, 590, 216861. doi:10.1016/j.canlet.2024.216861. https://pubmed.ncbi.nlm.nih.gov/38583649/

3. Hua, Tong, Yang, Mei, Song, Honghao, Wang, Yue, Yuan, Hongbin. 2022. Huc-MSCs-derived exosomes attenuate inflammatory pain by regulating microglia pyroptosis and autophagy via the miR-146a-5p/TRAF6 axis. In Journal of nanobiotechnology, 20, 324. doi:10.1186/s12951-022-01522-6. https://pubmed.ncbi.nlm.nih.gov/35836229/

4. Wu, Hua, Lu, Xing-Xing, Wang, Jing-Ru, Guo, Peng-Da, Li, Jian-Ming. 2019. TRAF6 inhibits colorectal cancer metastasis through regulating selective autophagic CTNNB1/β-catenin degradation and is targeted for GSK3B/GSK3β-mediated phosphorylation and degradation. In Autophagy, 15, 1506-1522. doi:10.1080/15548627.2019.1586250. https://pubmed.ncbi.nlm.nih.gov/30806153/

5. Zeng, Feier, Carrasco, Giovana, Li, Boya, Sophocleous, Antonia, Idris, Aymen I. 2023. TRAF6 as a potential target in advanced breast cancer: a systematic review, meta-analysis, and bioinformatics validation. In Scientific reports, 13, 4646. doi:10.1038/s41598-023-31557-0. https://pubmed.ncbi.nlm.nih.gov/36944688/

6. Matsui, Shinichiro, Ri, Chihiro, Bolanos, Lyndsey C, Sakaida, Emiko, Muto, Tomoya. 2024. Metabolic reprogramming regulated by TRAF6 contributes to the leukemia progression. In Leukemia, 38, 1032-1045. doi:10.1038/s41375-024-02245-3. https://pubmed.ncbi.nlm.nih.gov/38609495/