A role of PIEZO1 in iron metabolism in mice and humans.
A role of PIEZO1 in iron metabolism in mice and humans.
复制标题
DOI：
10.1016/j.cell.2021.01.024
复制
发表时间：
2021-02-18
期刊：
影响因子：
64.5
通讯作者：
Patapoutian A
中科院分区：
文献类型：
--
作者：
Ma S;Dubin AE;Zhang Y;Mousavi SAR;Wang Y;Coombs AM;Loud M;Andolfo I;Patapoutian A
铁超负荷导致进行性器官损伤，并与包括关节炎，肝脏和心脏衰竭在内的疾病有关。铁水平升高存在于1-5%的个体中;然而，铁过载被监测和诊断不足。影响铁稳态的遗传因素正在出现。遗传性干细胞症是一种罕见的疾病，在机械敏感性PIEZO 1离子通道中存在功能获得性（GOF）突变，其个体会发生年龄性铁过载。我们表明，组成或巨噬细胞表达的GOF Piezo 1等位基因在小鼠中破坏铁调节铁调素的水平，并导致铁过载。我们进一步表明，PIEZO 1是巨噬细胞吞噬活性和随后的红细胞周转的关键调节因子。引人注目的是，我们发现E756 del，一个温和的GOF PIEZO 1等位基因存在于三分之一的非洲裔个体中，与血浆铁增加密切相关。我们的研究将巨噬细胞机械转导与铁代谢联系起来，并确定了非裔美国人铁水平升高的遗传风险因素。
Iron overload causes progressive organ damage and is associated with diseases including arthritis, liver and heart failure. Elevated iron levels are present in 1–5% of individuals; however, iron overload is undermonitored and underdiagnosed. Genetic factors affecting iron homeostasis are emerging. Individuals with hereditary xerocytosis, a rare disorder with gain-of-function (GOF) mutations in mechanosensitive PIEZO1 ion channel, develop age-onset iron overload. We show that constitutive or macrophage expression of a GOF Piezo1 allele in mice disrupts levels of the iron regulator hepcidin and causes iron overload. We further show that PIEZO1 is a key regulator of macrophage phagocytic activity and subsequent erythrocyte turnover. Strikingly, we find that E756del, a mild GOF PIEZO1 allele present in a third of individuals of African descent, is strongly associated with increased plasma iron. Our study links macrophage mechanotransduction to iron metabolism and identifies a genetic risk factor for increased iron level in African Americans.
登录
查看更多内容
影响因子：
64.8
作者：
Gurdasani, Deepti;Carstensen, Tommy;Tekola-Ayele, Fasil;Pagani, Luca;Tachmazidou, Ioanna;Hatzikotoulas, Konstantinos;Karthikeyan, Savita;Iles, Louise;Pollard, Martin O.;Choudhury, Ananyo;Ritchie, GrahamR. S.;Xue, Yali;Asimit, Jennifer;Nsubuga, Rebecca N.;Young, Elizabeth H.;Pomilla, Cristina;Kivinen, Katja;Rockett, Kirk;Kamali, Anatoli;Doumatey, Ayo P.;Asiki, Gershim;Seeley, Janet;Sisay-Joof, Fatoumatta;Jallow, Muminatou;Tollman, Stephen;Mekonnen, Ephrem;Ekong, Rosemary;Oljira, Tamiru;Bradman, Neil;Bojang, Kalifa;Ramsay, Michele;Adeyemo, Adebowale;Bekele, Endashaw;Motala, Ayesha;Norris, Shane A.;Pirie, Fraser;Kaleebu, Pontiano;Kwiatkowski, Dominic;Tyler-Smith, Chris;Rotimi, Charles;Zeggini, Eleftheria;Sandhu, Manjinder S.
通讯作者：
Sandhu, Manjinder S.
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
29
作者：
Donovan, A;Lima, CA;Andrews, NC
通讯作者：
Andrews, NC
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
158.5
作者：
Adams, PC;Reboussin, DM;Thomson, E
通讯作者：
Thomson, E