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Haematologica. 2019 Oct;104(10):1984-1994. doi: 10.3324/haematol.2018.203992. Epub 2019 Feb 28.

Deletion of a flippase subunit Tmem30a in hematopoietic cells impairs mouse fetal liver erythropoiesis.

Author information

1
Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China.
2
Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
3
Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA.
4
School of Life Science, Zhengzhou University, Zhengzhou, China.
5
Division of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
6
The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China and Chengdu, Sichuan, China.
7
Chengdu Institute of Biology, Sichuan Translational Medicine Research Hospital, Chinese Academy of Sciences, Chengdu, China.
8
Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
9
Laboratory of Blood-Borne Parasites, New York Blood Center, New York, NY, USA.
10
Laboratory of Complement Biology, New York Blood Center, New York, NY, USA.
11
Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China xan@nybc.org.
12
Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China zhenyuju@163.com.
13
Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China.

Abstract

Transmembrane protein 30A (Tmem30a) is the β-subunit of P4-ATPases which function as flippase that transports aminophospholipids such as phosphatidylserine from the outer to the inner leaflets of the plasma membrane to maintain asymmetric distribution of phospholipids. It has been documented that deficiency of Tmem30a led to exposure of phosphatidylserine. However, the role of Tmem30a in vivo remains largely unknown. Here we found that Vav-Cre-driven conditional deletion of Tmem30a in hematopoietic cells led to embryonic lethality due to severe anemia by embryonic day 16.5. The numbers of erythroid colonies and erythroid cells were decreased in the Tmem30a deficient fetal liver. This was accompanied by increased apoptosis of erythroid cells. Confocal microscopy analysis revealed an increase of localization of erythropoietin receptor to areas of membrane raft microdomains in response to erythropoietin stimulation in Ter119-erythroid progenitors, which was impaired in Tmem30a deficient cells. Moreover, erythropoietin receptor (EPOR)-mediated activation of the STAT5 pathway was significantly reduced in Tmem30a deficient fetal liver cells. Consistently, knockdown of TMEM30A in human CD34+ cells also impaired erythropoiesis. Our findings demonstrate that Tmem30a plays a critical role in erythropoiesis by regulating the EPOR signaling pathway through the formation of membrane rafts in erythroid cells.

PMID:
30819915
DOI:
10.3324/haematol.2018.203992
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