Deubiquitylase USP7 regulates human terminal erythroid differentiation by stabilizing GATA1
Long Liang,
Yuanliang Peng,
Jieying Zhang,
Yibin Zhang,
Mridul Roy,
Xu Han,
Xiaojuan Xiao,
Shuming Sun,
Hong Liu,
Ling Nie,
Yijin Kuang,
Zesen Zhu,
Jinghui Deng,
Yang Xia,
Vijay G. Sankaran,
Christopher D. Hillyer,
Narla Mohandas,
Mao Ye,
Xiuli An,
Jing Liu
Affiliations
Long Liang
Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China;Molecular 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
Yuanliang Peng
Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
Jieying Zhang
Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China;Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA
Yibin Zhang
Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China;Molecular 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
Mridul Roy
Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China;Molecular 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
Xu Han
Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
Xiaojuan Xiao
Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
Shuming Sun
Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
Hong Liu
Xiangya Hospital, Central South University, Changsha, China
Ling Nie
Xiangya Hospital, Central South University, Changsha, China
Yijin Kuang
Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
Zesen Zhu
Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
Jinghui Deng
Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
Yang Xia
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX, USA
Vijay G. Sankaran
Broad Institute of MIT and Harvard, Cambridge, MA, USA;Division of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Christopher D. Hillyer
Red Cell Physiology Laboratory, New York Blood Center, New York, NY, USA
Narla Mohandas
Red Cell Physiology Laboratory, New York Blood Center, New York, NY, USA
Mao Ye
Molecular 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
Xiuli An
Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA;School of Life Sciences, Zhengzhou University, Zhengzhou, China
Jing Liu
Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China;Erythropoiesis Research Center, Central South University, Changsha, China
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 reticulocyte 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 erythropoiesis 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 interfering with USP7 function, either by short hairpin RNA-mediated knockdown or USP7-specific inhibitors, impaired human terminal erythroid differentiation due to decreased GATA1 level and that restoration of GATA1 levels rescued 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 poly ubiquitylation 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.
