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

Abstract

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.

G protein pathway suppressor 2 suppresses gastric cancer by destabilizing epidermal growth factor receptor

“…As a critical subunit of the NCOR/SMRT complex, GPS2 is mainly located in the nucleus. 17 Recent studies have shown that GPS2 plays important roles in the cytoplasm, including promoting erythroid differentiation by controlling the stability of the EKLF protein 34 and regulating multiple stages of B cell development by inhibiting Ubc13‐mediated ubiquitination. 35 However, few studies have explored the relationship between the expression of GPS2 and the progression and prognosis of cancer.…”

Autophagy regulated by the HIF/REDD1/mTORC1 signaling is progressively increased during erythroid differentiation under hypoxia

“…Giemsa stain assay was performed as previously described ( Ma et al, 2020 ). Briefly, the cells were collected by centrifugation and resuspended in PBS at different times of differentiation.…”

A Review of Key Regulators of Steady-State and Ineffective Erythropoiesis

“…Key molecular participants in these networks encompass iron, regulators of iron metabolism like transferrin receptors-1 and -2, as well as early acting hematopoietic growth factors including stem cell factor and interleukin-3. Additionally, classical hormones like thyroid hormones, androgens, corticosteroids, activin/inhibin, and others are integral components [30][31][32][33][34].…”