TRIB2, a pseudo serine/threonine kinase, is a member of the Tribbles family of pseudokinase proteins. It functions as a scaffold or adaptor, playing crucial roles in multiple biological processes. TRIB2 is involved in the ubiquitin-proteasome degradation system, regulating protein homeostasis of key factors like C/EBPα, β-catenin, and TCF4. It also interacts with proteins in the MAPKK, AKT, and NF-κB signaling pathways, influencing cell survival, proliferation, and immune response [2,3,5].

In naive T-cell homeostasis, TRIB2 is more abundant in naive CD4+ than CD8+ T-cells. Its deficiency in mice leads to increased AKT activity, accelerating proliferation and differentiation in response to interleukin-7 (IL-7) in humans and during lymphopenia in mice. In older adults, the waning of ThPOK and TRIB2 expression in naive CD4+ T-cells causes loss of naivety, highlighting its role in T-cell homeostasis [1]. In cancer, TRIB2 has been well-characterized for its role in murine and human leukemia, lung, and liver cancer. For example, in liver cancer cells, deletion of TRIB2 sensitizes ferroptosis via lifting labile iron, while overexpression desensitizes ferroptosis through βTrCP-mediated TFRC ubiquitination [2,4]. In gastric cancer with a CIN phenotype, overexpression of TRIB2 reduces cell proliferation, colony formation, and cell motility, suggesting a tumor-suppressive function [6].

In summary, TRIB2 is essential for maintaining T-cell homeostasis during aging. In cancer, its role varies depending on the cancer type, either promoting or suppressing tumorigenesis. Gene knockout models in mice have been instrumental in revealing these functions, providing valuable insights into T-cell-related diseases and cancer biology, and potentially guiding the development of novel therapeutic strategies.

References:

1. Cao, Wenqiang, Sturmlechner, Ines, Zhang, Huimin, Weyand, Cornelia M, Goronzy, Jörg J. 2023. TRIB2 safeguards naive T cell homeostasis during aging. In Cell reports, 42, 112195. doi:10.1016/j.celrep.2023.112195. https://pubmed.ncbi.nlm.nih.gov/36884349/

2. Salomè, Mara, Campos, Joana, Keeshan, Karen. . TRIB2 and the ubiquitin proteasome system in cancer. In Biochemical Society transactions, 43, 1089-94. doi:10.1042/BST20150103. https://pubmed.ncbi.nlm.nih.gov/26517929/

3. Mayoral-Varo, Victor, Jiménez, Lucía, Link, Wolfgang. 2021. The Critical Role of TRIB2 in Cancer and Therapy Resistance. In Cancers, 13, . doi:10.3390/cancers13112701. https://pubmed.ncbi.nlm.nih.gov/34070799/

4. Guo, Susu, Chen, Yuxin, Xue, Xiangfei, Qiao, Yongxia, Wang, Jiayi. 2021. TRIB2 desensitizes ferroptosis via βTrCP-mediated TFRC ubiquitiantion in liver cancer cells. In Cell death discovery, 7, 196. doi:10.1038/s41420-021-00574-1. https://pubmed.ncbi.nlm.nih.gov/34315867/

5. Fang, Yu, Zekiy, Angelina Olegovna, Ghaedrahmati, Farhoodeh, Anbiyaiee, Amir, Khoshnam, Seyed Esmaeil. 2021. Tribbles homolog 2 (Trib2), a pseudo serine/threonine kinase in tumorigenesis and stem cell fate decisions. In Cell communication and signaling : CCS, 19, 41. doi:10.1186/s12964-021-00725-y. https://pubmed.ncbi.nlm.nih.gov/33794905/

6. Foscarini, Alessia, Tricarico, Rossella, Gentile, Federica, Ranzani, Guglielmina Nadia, Pellegata, Natalia Simona. 2023. Tribbles Genes in Gastric Cancer: A Tumor-Suppressive Role for TRIB2. In Genes, 15, . doi:10.3390/genes15010026. https://pubmed.ncbi.nlm.nih.gov/38254916/