GPS2 promotes erythroid differentiation by control of the stability of EKLF protein.

Blood 2020 Jun 18

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Erythropoiesis is a complex multistage process that involves differentiation of early erythroid progenitors to enucleated mature red blood cells, in which lineage-specific transcription factors play essential roles. Erythroid Krüppel-like factor (EKLF/KLF1) is a pleiotropic erythroid transcription factor that is required for the proper maturation of the erythroid cells, whose expression and activation are tightly controlled in a temporal and differentiation stage-specific manner. Here, we uncover a novel role of G-protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor/silencing mediator of retinoic acid and thyroid hormone receptor corepressor complex, in erythrocyte differentiation. Our study demonstrates that knockdown of GPS2 significantly suppresses erythroid differentiation of human CD34+ cells cultured in vitro and xenotransplanted in nonobese diabetic/severe combined immunodeficiency/interleukin-2 receptor γ-chain null mice. Moreover, global deletion of GPS2 in mice causes impaired erythropoiesis in the fetal liver and leads to severe anemia. Flow cytometric analysis and Wright-Giemsa staining show a defective differentiation at late stages of erythropoiesis in Gps2-/- embryos. Mechanistically, GPS2 interacts with EKLF and prevents proteasome-mediated degradation of EKLF, thereby increasing EKLF stability and transcriptional activity. Moreover, we identify the amino acids 191-230 region in EKLF protein, responsible for GPS2 binding, that is highly conserved in mammals and essential for EKLF protein stability. Collectively, our study uncovers a previously unknown role of GPS2 as a posttranslational regulator that enhances the stability of EKLF protein and thereby promotes erythroid differentiation. © 2020 by The American Society of Hematology.

Citation

Wen-Bing Ma, Xiao-Han Wang, Chang-Yan Li, Huan-Huan Tian, Jie Zhang, Jun-Jie Bi, Guang-Ming Ren, Shou-Song Tao, Xian Liu, Wen Zhang, Dong-Xu Li, Hui Chen, Yi-Qun Zhan, Miao Yu, Chang-Hui Ge, Xiao-Ming Yang, Rong-Hua Yin. GPS2 promotes erythroid differentiation by control of the stability of EKLF protein. Blood. 2020 Jun 18;135(25):2302-2315