The TMC genes encode a set of homologous transmembrane proteins whose functions are not well understood. Biallelic mutations in either TMC6 or TMC8 are detected in more than half of cases of the pre-malignant skin disease epidermodysplasia verruciformis (EV). It is controversial whether EV induced by mutations in TMC6 or TMC8 originates from keratinocyte or lymphocyte defects. Quantification of TMC6 and TMC8 RNA levels in various organs revealed that lymphoid tissues have the highest levels of expression of both genes, and custom antibodies confirmed protein expression in mouse lymphocytes. To study the function of these proteins we generated mice with targeted deletion mutant alleles of Tmc6 or Tmc8. Either TMC6 or TMC8 deficiency induced a reduction in apparent molecular weight and/or amount of the other TMC molecule. Co-immunoprecipitation experiments indicated that TMC6 and TMC8 formed a protein complex in mouse and human T cells. MS and biochemical analysis demonstrated that TMC6 and TMC8 additionally interacted with the CIB1 protein to form TMC6-TMC8-CIB1 trimers. We demonstrated that TMC6 and TMC8 regulated CIB1 levels by protecting CIB1 from ubiquitination and proteasomal degradation. Reciprocally, CIB1 was needed for stabilizing TMC6 and TMC8 levels. These results suggest why inactivating mutations in any of the three human genes leads to similar clinical presentations. We also demonstrated that TMC6 and TMC8 levels are drastically lower and the proteins are less active in regulating CIB1 in keratinocytes than in T cells. Our study suggests that defects in lymphocytes may contribute to the etiology and pathogenesis of EV.

中文翻译：

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TMC6-TMC8-CIB1 异源三聚体复合物在淋巴细胞中的表达受每种成分的调节。

TMC 基因编码一组同源跨膜蛋白，其功能尚不清楚。在超过一半的恶性前皮肤病表皮发育不良 (EV) 病例中检测到 TMC6 或 TMC8 中的双等位基因突变。由 TMC6 或 TMC8 突变诱导的 EV 是否起源于角质形成细胞或淋巴细胞缺陷尚存在争议。对不同器官中 TMC6 和 TMC8 RNA 水平的定量显示，淋巴组织具有最高水平的两种基因表达，定制抗体证实了小鼠淋巴细胞中的蛋白质表达。为了研究这些蛋白质的功能，我们生成了具有 Tmc6 或 Tmc8 的靶向缺失突变等位基因的小鼠。TMC6 或 TMC8 缺陷导致表观分子量和/或其他 TMC 分子的量减少。免疫共沉淀实验表明 TMC6 和 TMC8 在小鼠和人类 T 细胞中形成蛋白质复合物。MS和生化分析表明，TMC6和TMC8还与CIB1蛋白相互作用形成TMC6-TMC8-CIB1三聚体。我们证明 TMC6 和 TMC8 通过保护 CIB1 免受泛素化和蛋白酶体降解来调节 CIB1 水平。相反，需要 CIB1 来稳定 TMC6 和 TMC8 水平。这些结果表明，为什么三个人类基因中的任何一个失活突变都会导致相似的临床表现。我们还证明 TMC6 和 TMC8 水平显着降低，并且这些蛋白质在调节角质形成细胞中的 CIB1 方面的活性低于 T 细胞。我们的研究表明，淋巴细胞缺陷可能与 EV 的病因和发病机制有关。