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Haematologica 2019 Volume 104(11):2178-2188
Red Cell Biology & its Disorders
Deubiquitylase USP7 regulates human terminal erythroid differentiation
by stabilizing GATA1
Long Liang,1,2 Yuanliang Peng,1 Jieying Zhang,1,3 Yibin Zhang,1,2 Mridul Roy,1,2 Xu Han,1 Xiaojuan Xiao,1 Shuming Sun,1 Hong Liu,4 Ling Nie,4 Yijin Kuang,1 Zesen Zhu,1 Jinghui Deng,1 Yang Xia,5 Vijay G. Sankaran,6,7 Christopher D. Hillyer,8 Narla Mohandas,8 Mao Ye,2 Xiuli An3,9 and Jing Liu1,10
1Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China; 2Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha, China; 3Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA; 4Xiangya Hospital, Central South University, Changsha, China; 5Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX, USA; 6Broad Institute of MIT and Harvard, Cambridge, MA, USA; 7Division of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 8Red Cell Physiology Laboratory, New York Blood Center, New York, NY, USA; 9School of Life Sciences, Zhengzhou University, Zhengzhou, China and 10Erythropoiesis Research Center, Central South University, Changsha, China
ABSTRACT
Ubiquitination is an enzymatic post-translational modification that affects protein fate. The ubiquitin-proteasome system (UPS) was first discovered in reticulocytes where it plays important roles in reticulo- cyte maturation. Recent studies have revealed that ubiquitination is a dynamic and reversible process and that deubiquitylases are capable of removing ubiquitin from their protein substrates. Given the fact that the UPS is highly active in reticulocytes, it is speculated that deubiquitylases may play important roles in erythropoiesis. Yet, the role of deubiquitylases in ery- thropoiesis remains largely unexplored. In the present study, we found that the expression of deubiquitylase USP7 is significantly increased during human terminal erythroid differentiation. We further showed that interfer- ing with USP7 function, either by short hairpin RNA-mediated knockdown or USP7-specific inhibitors, impaired human terminal erythroid differentia- tion due to decreased GATA1 level and that restoration of GATA1 levels res- cued the differentiation defect. Mechanistically, USP7 deficiency led to a decreased GATA1 protein level that could be reversed by proteasome inhibitors. Furthermore, USP7 interacts directly with GATA1 and catalyzes the removal of K48-linked polyubiquitylation chains conjugated onto GATA1, thereby stabilizing GATA1 protein. Collectively, our findings have identified an important role of a deubiquitylase in human terminal erythroid differentiation by stabilizing GATA1, the master regulator of erythropoiesis.
Introduction
Red blood cells, the most abundant of all circulating blood cells, facilitate gas exchange in the lungs and transporting oxygen to tissues. More than two million red blood cells are generated per second in a healthy adult through a process termed ery- thropoiesis. Mature red blood cells are produced from hematopoietic stem cells, which commit to erythroid progenitors followed by terminal erythroid differentia- tion. Terminal erythroid differentiation, driven by the glycoprotein hormone ery- thropoietin, begins with proerythroblasts, which sequentially divide into basophilic, polychromatic and orthochromatic erythroblasts that enucleate to generate reticulo- cytes.1,2 Erythropoiesis is a tightly regulated process. Previous studies were primarily focused on the regulation of erythropoiesis by transcription factors and cytokines.3,4
Correspondence:
JING LIU
jingliucsu@hotmail.com or liujing2@sklmg.edu.cn
XIULI AN
xan@nybc.org
MAO YE
goldleaf@hnu.edu.cn
Received: September 8, 2018. Accepted: March 13, 2019. Pre-published: March 14, 2019.
doi:10.3324/haematol.2018.206227
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