Tmco6, short for transmembrane and coiled-coil domains 6, has its function being gradually elucidated. It is involved in multiple biological processes. In CD8+ T cells, it may be associated with immune-related pathways, and its potential interaction with other proteins like ubiquilin 1 implies its possible role in neurodegenerative-related processes [1,2].

In hepatocellular carcinoma (HCC), DNA of neutrophil extracellular traps (NET-DNA) binds to TMCO6 on CD8+ T cells. This binding impairs antitumor immunity, promotes HCC progression by inhibiting CD8+ T-cell function, increasing apoptosis and TGFβ1 secretion, and forming a positive feedback loop for further immunosuppression. Mechanistically, the N-terminus of TMCO6 interacts with NET-DNA, suppressing T-cell receptor signaling and NFκB p65 nuclear translocation. Blocking NET formation by inhibiting PAD4 shows potent antitumor effects in wild-type mice but not in TMCO6-/-mice, indicating TMCO6 is crucial in this process [1]. In North Country Cheviot sheep, a homozygous loss-of-function variant in the ovine TMCO6 gene leads to early-onset progressive ataxia and motor neuron degeneration, providing a genetic model for studying TMCO6-related neurodegenerative diseases [2].

In summary, TMCO6 plays a significant role in immune regulation in HCC, potentially through its interaction with NET-DNA on CD8+ T cells. The gene knockout models in mice and the loss-of-function variant in sheep have revealed its importance in tumor-related immune response and neurodegenerative disease conditions, which contributes to a better understanding of the underlying mechanisms and potential therapeutic targets for these diseases.

References:

1. Song, Mengjia, Zhang, Chaoqi, Cheng, Shaoyan, Zhang, Yizhuo, Xia, Jian-Chuan. . DNA of Neutrophil Extracellular Traps Binds TMCO6 to Impair CD8+ T-cell Immunity in Hepatocellular Carcinoma. In Cancer research, 84, 1613-1629. doi:10.1158/0008-5472.CAN-23-2986. https://pubmed.ncbi.nlm.nih.gov/38381538/

2. Letko, Anna, Brülisauer, Franz, Häfliger, Irene M, Scholes, Sandra, Drögemüller, Cord. 2023. Loss-of-function variant in the ovine TMCO6 gene in North Country Cheviot sheep with motor neuron disease. In Genomics, 115, 110689. doi:10.1016/j.ygeno.2023.110689. https://pubmed.ncbi.nlm.nih.gov/37488055/