A role for the <i>Drosophila</i> zinc transporter <i>Zip88E</i> in protecting against dietary zinc toxicity

Zinc absorption in animals is thought to be regulated in a local, cell autonomous manner with intestinal cells responding to dietary zinc content. The Drosophila zinc transporter Zip88E shows strong sequence similarity to Zips 42C.1, 42C.2 and 89B as well as mammalian Zips 1, 2 and 3, suggesting that it may act in concert with the apically-localised Drosophila zinc uptake transporters to facilitate dietary zinc absorption by importing ions into the midgut enterocytes. However, the functional characterisation of Zip88E presented here indicates that Zip88E may instead play a role in detecting and responding to zinc toxicity. Larvae homozygous for a null Zip88E allele are viable yet display heightened sensitivity to elevated levels of dietary zinc. This decreased zinc tolerance is accompanied by an overall decrease in Metallothionein B transcription throughout the larval midgut. A Zip88E reporter gene is expressed only in the salivary glands, a handful of enteroendocrine cells at the boundary between the anterior and middle midgut regions, and in two parallel strips of sensory cell projections connecting to the larval ventral ganglion. Zip88E expression solely in this restricted subset of cells is sufficient to rescue the Zip88E mutant phenotype. Together, our data suggest that Zip88E may be functioning in a small subset of cells to detect excessive zinc levels and induce a systemic response to reduce dietary zinc absorption and hence protect against toxicity.学界普遍认为，动物体内的锌吸收受局部细胞自主调控机制支配，肠上皮细胞可响应膳食锌浓度变化。果蝇锌转运蛋白Zip88E与Zips 42C.1、42C.2及89B，以及哺乳动物Zips 1、2、3均具有较高序列同源性，这提示其可能与顶膜定位的果蝇锌摄取转运蛋白协同作用，通过将锌离子转运至中肠肠上皮细胞，促进膳食锌的吸收。但本研究开展的Zip88E功能表征实验结果显示，该蛋白或在检测并响应锌毒性过程中发挥作用。携带纯合缺失型Zip88E等位基因的幼虫可正常存活，但对膳食锌浓度升高的敏感性显著增强。这种锌耐受能力下降的表型，伴随幼虫中肠内金属硫蛋白B（Metallothionein B）转录水平的整体下调。Zip88E报告基因仅在唾液腺、前中肠与中中肠区域边界处的少量肠内分泌细胞，以及两条连接至幼虫腹神经节的平行感觉细胞投射束中表达。仅在这一受限细胞亚群中恢复Zip88E的表达，即可挽救Zip88E突变体的异常表型。综上，本研究数据表明，Zip88E或在少量特定细胞亚群中发挥功能，通过检测过量锌水平并诱导全身反应，以降低膳食锌吸收，从而抵御锌毒性损伤。