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非洲中心主义的 TP53 变体增加了铁的积累和细菌发病机制，但改善了对疟疾毒素的反应。

African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin.

机构信息

Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, 19104, USA.

Department of Genetics, The Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.

出版信息

Nat Commun. 2020 Jan 24;11(1):473. doi: 10.1038/s41467-019-14151-9.

DOI:10.1038/s41467-019-14151-9
PMID:31980600
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6981190/
Abstract

A variant at amino acid 47 in human TP53 exists predominantly in individuals of African descent. P47S human and mouse cells show increased cancer risk due to defective ferroptosis. Here, we show that this ferroptotic defect causes iron accumulation in P47S macrophages. This high iron content alters macrophage cytokine profiles, leads to higher arginase level and activity, and decreased nitric oxide synthase activity. This leads to more productive intracellular bacterial infections but is protective against malarial toxin hemozoin. Proteomics of macrophages reveal decreased liver X receptor (LXR) activation, inflammation and antibacterial defense in P47S macrophages. Both iron chelators and LXR agonists improve the response of P47S mice to bacterial infection. African Americans with elevated saturated transferrin and serum ferritin show higher prevalence of the P47S variant (OR = 1.68 (95%CI 1.07-2.65) p = 0.023), suggestive of its role in iron accumulation in humans. This altered macrophage phenotype may confer an advantage in malaria-endemic sub-Saharan Africa.

摘要

人类 TP53 氨基酸 47 位的变异主要存在于非洲裔个体中。P47S 人类和小鼠细胞由于铁死亡缺陷而显示出更高的癌症风险。在这里，我们表明这种铁死亡缺陷导致 P47S 巨噬细胞中铁的积累。这种高铁含量改变了巨噬细胞细胞因子谱，导致精氨酸酶水平和活性增加，而一氧化氮合酶活性降低。这导致更具传染性的细胞内细菌感染，但对疟原虫毒素血影蛋白具有保护作用。巨噬细胞的蛋白质组学研究表明，P47S 巨噬细胞中的肝 X 受体 (LXR) 激活、炎症和抗菌防御减少。铁螯合剂和 LXR 激动剂均可改善 P47S 小鼠对细菌感染的反应。转铁蛋白饱和度和血清铁蛋白升高的非裔美国人中，P47S 变异的发生率更高（OR=1.68（95%CI 1.07-2.65）p=0.023），提示其在人类铁积累中的作用。这种改变的巨噬细胞表型可能在疟疾流行的撒哈拉以南非洲地区赋予优势。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fdaa/6981190/f3f276fb8b9e/41467_2019_14151_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fdaa/6981190/cd1189dc8cbb/41467_2019_14151_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fdaa/6981190/fca7ba60eb1b/41467_2019_14151_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fdaa/6981190/dc9fcc0f4d8d/41467_2019_14151_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fdaa/6981190/1522c2674aca/41467_2019_14151_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fdaa/6981190/3ba775a83226/41467_2019_14151_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fdaa/6981190/f3f276fb8b9e/41467_2019_14151_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fdaa/6981190/cd1189dc8cbb/41467_2019_14151_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fdaa/6981190/fca7ba60eb1b/41467_2019_14151_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fdaa/6981190/dc9fcc0f4d8d/41467_2019_14151_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fdaa/6981190/1522c2674aca/41467_2019_14151_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fdaa/6981190/3ba775a83226/41467_2019_14151_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fdaa/6981190/f3f276fb8b9e/41467_2019_14151_Fig6_HTML.jpg

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