Hemozoin produced by mammals confers heme tolerance

Author:

Pek Rini H12ORCID,Yuan Xiaojing12ORCID,Rietzschel Nicole12,Zhang Jianbing12,Jackson Laurie3,Nishibori Eiji45,Ribeiro Ana12,Simmons William6,Jagadeesh Jaya6,Sugimoto Hiroshi7ORCID,Alam Md Zahidul8,Garrett Lisa9,Haldar Malay8,Ralle Martina10,Phillips John D3,Bodine David M6,Hamza Iqbal12ORCID

Affiliation:

1. Department of Animal and Avian Sciences, University of Maryland, College Park, United States

2. Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, United States

3. Department of Medicine, University of Utah School of Medicine, Salt Lake City, United States

4. Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan

5. Tsukuba Research Center for Energy Materials Science, University of Tsukaba, Tsukaba, Japan

6. Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, United States

7. RIKEN SPring-8 Center, Sayo, Hyogo, Japan

8. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States

9. NHGRI Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, United States

10. Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, United States

Abstract

Free heme is cytotoxic as exemplified by hemolytic diseases and genetic deficiencies in heme recycling and detoxifying pathways. Thus, intracellular accumulation of heme has not been observed in mammalian cells to date. Here we show that mice deficient for the heme transporter SLC48A1 (also known as HRG1) accumulate over ten-fold excess heme in reticuloendothelial macrophage lysosomes that are 10 to 100 times larger than normal. Macrophages tolerate these high concentrations of heme by crystallizing them into hemozoin, which heretofore has only been found in blood-feeding organisms. SLC48A1 deficiency results in impaired erythroid maturation and an inability to systemically respond to iron deficiency. Complete heme tolerance requires a fully-operational heme degradation pathway as haplo insufficiency of HMOX1 combined with SLC48A1 inactivation causes perinatal lethality demonstrating synthetic lethal interactions between heme transport and degradation. Our studies establish the formation of hemozoin by mammals as a previously unsuspected heme tolerance pathway.

Funder

National Institute of Diabetes and Digestive and Kidney Diseases

National Institute of Environmental Health Sciences

National Human Genome Research Institute

Department of Energy

Japan Synchrotron Radiation Research Institute

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

Reference70 articles.

1. Heatmapper: web-enabled heat mapping for all;Babicki;Nucleic Acids Research,2016

2. Lysosome transport as a function of lysosome diameter;Bandyopadhyay;PLOS ONE,2014

3. Pyridine hemochromagen assay for determining the concentration of heme in purified protein solutions;Barr;Bio-Protocol,2015

4. Synergistic and antagonistic interactions between haemozoin and bacterial endotoxin on human and mouse macrophages;Basilico;Parassitologia,2003

5. Recycling iron in normal and pathological states;Beaumont;Seminars in Hematology,2009

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3