Kctd9, belonging to the potassium channel tetramerization domain-containing (KCTD) gene family, functions as a Cullin3-dependent E3 ligase [3]. It is involved in multiple biological processes and associated with pathways like the Wnt/β-catenin pathway [2]. Understanding its function is crucial as it impacts cell development, function, and disease progression. Genetic models, such as gene-knockout mice, are valuable for studying Kctd9.

Using Kctd9-knockout mice, studies revealed that Kctd9 is essential for natural killer (NK) cell development and function. Kctd9-deficient mice showed impaired NK cell lineage commitment and incomplete maturation. Kctd9-depleted NK cells had insufficient IFN-γ production, degranulation, and granzyme B production, and attenuated cytotoxicity to tumor cells. These defects led to ameliorated liver damage and improved survival in Kctd9-deficient mice following MHV-3 infection, similar to the phenotype of NK cell-depleted wild-type mice. Mechanistically, Kctd9 deficiency hindered the expression of transcription factors like Ets1, Nfil3, Eomes, and Id2 in NK cells [1]. In colorectal cancer, KCTD9 overexpression inhibited cell proliferation and metastasis by decreasing β-catenin levels and inactivating the Wnt/β-catenin pathway, while knockdown promoted these processes [2].

In conclusion, Kctd9 is a key regulator of NK cell commitment, maturation, and effector function. Its role in NK cell-related liver injury and as a potential tumor suppressor in colorectal cancer, as revealed by knockout mouse models, provides important insights into the pathogenesis of these diseases and potential therapeutic targets.

References:

1. Zhang, Xiaoping, Wang, Peng, Chen, Tao, Wan, Xiaoyang, Ning, Qin. 2019. Kctd9 Deficiency Impairs Natural Killer Cell Development and Effector Function. In Frontiers in immunology, 10, 744. doi:10.3389/fimmu.2019.00744. https://pubmed.ncbi.nlm.nih.gov/31024568/

2. Yao, Hanhui, Ren, Delong, Wang, Yichun, Li, Qidong, Liu, Lianxin. 2022. KCTD9 inhibits the Wnt/β-catenin pathway by decreasing the level of β-catenin in colorectal cancer. In Cell death & disease, 13, 761. doi:10.1038/s41419-022-05200-1. https://pubmed.ncbi.nlm.nih.gov/36055981/

3. Pinkas, Daniel M, Sanvitale, Caroline E, Bufton, Joshua C, Doutch, James, Bullock, Alex N. 2017. Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases. In The Biochemical journal, 474, 3747-3761. doi:10.1042/BCJ20170527. https://pubmed.ncbi.nlm.nih.gov/28963344/