Tmc8, also known as EVER2, is a gene encoding a transmembrane protein. It is part of the transmembrane channel-like (TMC) protein family, sharing homology with anoctamin 1. Tmc8 is involved in regulating intracellular signaling by attenuating Zn²⁺ and Ca²⁺ signaling and suppressing the activation of Cl⁻ currents [5]. Mutations in Tmc8 are associated with epidermodysplasia verruciformis (EV), a genodermatosis that leads to susceptibility to cutaneous HPV infections, persistent plane warts, and a high rate of non-melanoma skin cancer [1,3,4,6].

Mice with targeted deletion mutant alleles of Tmc8 showed that TMC8 deficiency induced a reduction in the apparent molecular weight and/or amount of TMC6. TMC6 and TMC8 formed a protein complex in mouse and human T cells, and together with CIB1, they formed TMC6-TMC8-CIB1 trimers. These findings suggest that Tmc8 plays a role in the regulation of protein complex formation and lymphocyte function, which may contribute to the etiology and pathogenesis of EV [2].

In conclusion, Tmc8 is crucial for regulating intracellular signaling and protein complex formation. The study of Tmc8 knockout mouse models has revealed its role in EV, highlighting its importance in understanding the disease mechanism and potentially guiding the development of related treatment strategies.

References:

1. Imahorn, E, Yüksel, Z, Spoerri, I, Itin, P H, Burger, B. 2017. Novel TMC8 splice site mutation in epidermodysplasia verruciformis and review of HPV infections in patients with the disease. In Journal of the European Academy of Dermatology and Venereology : JEADV, 31, 1722-1726. doi:10.1111/jdv.14431. https://pubmed.ncbi.nlm.nih.gov/28646613/

2. Wu, Chuan-Jin, Li, Xing, Sommers, Connie L, Griffith, Andrew J, Samelson, Lawrence E. 2020. Expression of a TMC6-TMC8-CIB1 heterotrimeric complex in lymphocytes is regulated by each of the components. In The Journal of biological chemistry, 295, 16086-16099. doi:10.1074/jbc.RA120.013045. https://pubmed.ncbi.nlm.nih.gov/32917726/

3. Esenboga, Saliha, Cagdas, Deniz, Alkanat, Nazli Eylem, Boztug, Kaan, Tezcan, Ilhan. 2021. TMC8 mutation in a Turkish family with epidermodysplasia verruciformis including laryngeal papilloma and recurrent skin carcinoma. In Journal of cosmetic dermatology, 21, 2263-2267. doi:10.1111/jocd.14393. https://pubmed.ncbi.nlm.nih.gov/34416085/

4. Shimizu, Akira, Yamaguchi, Reimon, Kuriyama, Yuko. 2023. Recent advances in cutaneous HPV infection. In The Journal of dermatology, 50, 290-298. doi:10.1111/1346-8138.16697. https://pubmed.ncbi.nlm.nih.gov/36601717/

5. Sirianant, Lalida, Ousingsawat, Jiraporn, Tian, Yuemin, Schreiber, Rainer, Kunzelmann, Karl. 2014. TMC8 (EVER2) attenuates intracellular signaling by Zn2+ and Ca2+ and suppresses activation of Cl- currents. In Cellular signalling, 26, 2826-33. doi:10.1016/j.cellsig.2014.09.001. https://pubmed.ncbi.nlm.nih.gov/25220380/

6. Burger, B, Itin, P H. 2014. Epidermodysplasia verruciformis. In Current problems in dermatology, 45, 123-31. doi:10.1159/000356068. https://pubmed.ncbi.nlm.nih.gov/24643182/