The Department of Cell Biology, The Johns Hopkins University School of Medicine, 725 N. Wolfe St, Baltimore, MD, 21205, USA.
BMC Mol Cell Biol. 2019 Jun 26;20(1):19. doi: 10.1186/s12860-019-0198-z.
CG4552/tbc1 was identified as a downstream target of Fork head (Fkh), the single Drosophila member of the FoxA family of transcription factors and a major player in salivary gland formation and homeostasis. Tbc1 and its orthologues have been implicated in phagocytosis, the innate immune response, border cell migration, cancer and an autosomal recessive form of non-degenerative Pontocerebellar hypoplasia. Recently, the mammalian Tbc1 orthologue, Tbc1d23, has been shown to bind both the conserved N-terminal domains of two Golgins (Golgin-97 and Golgin-245) and the WASH complex on endosome vesicles. Through this activity, Tbc1d23 has been proposed to link endosomally-derived vesicles to their appropriate target membrane in the trans Golgi (TGN).
In this paper, we provide an initial characterization of Drosophila orthologue, we call tbc1. We show that, like its mammalian orthologue, Tbc1 localizes to the trans Golgi. We show that it also colocalizes with a subset of Rabs associated with both early and recycling endosomes. Animals completely missing tbc1 survive, but females have fertility defects. Consistent with the human disease, loss of tbc1 reduces optic lobe size and increases response time to mechanical perturbation. Loss and overexpression of tbc1 in the embryonic salivary glands leads to secretion defects and apical membrane irregularities.
These findings support a role for tbc1 in endocytic/membrane trafficking, consistent with its activities in other systems.
CG4552/tbc1 被鉴定为叉头（Fkh）的下游靶标，Fkh 是 FoxA 家族转录因子的果蝇单一成员，也是唾液腺形成和稳态的主要参与者。Tbc1 及其同源物与吞噬作用、先天免疫反应、边缘细胞迁移、癌症和非退行性桥小脑发育不良的常染色体隐性形式有关。最近，哺乳动物 Tbc1 同源物 Tbc1d23 已被证明可以结合两个 Golgin（Golgin-97 和 Golgin-245）的保守 N 端结构域和内体小泡上的 WASH 复合物。通过这种活性，Tbc1d23 被提议将内体衍生的小泡连接到它们在反高尔基（TGN）中的适当靶膜。
在本文中，我们对果蝇同源物 tbc1 进行了初步表征。我们表明，与哺乳动物同源物一样，Tbc1 定位于反高尔基。我们还表明，它还与与早期和再循环内体相关的一组 Rab 共定位。完全缺失 tbc1 的动物可以存活，但雌性具有生育缺陷。与人类疾病一致，tbc1 的缺失会减少视叶大小并增加对机械扰动的反应时间。在胚胎唾液腺中缺失和过表达 tbc1 会导致分泌缺陷和顶膜不规则。
这些发现支持 tbc1 在胞吞/膜运输中的作用，与其在其他系统中的活性一致。
