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1.
J Biol Chem ; : 107542, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38992436

RESUMO

Diamond Blackfan Anemia (DBA) is a rare macrocytic red blood cell aplasia that usually presents within the first year of life. The vast majority of patients carry a mutation in one of approximately 20 genes that results in ribosomal insufficiency with the most significant clinical manifestations being anemia and a predisposition to cancers. Nemo-like Kinase (NLK) is hyperactivated in the erythroid progenitors of DBA patients and inhibition of this kinase improves erythropoiesis, but how NLK contributes to the pathogenesis of the disease is unknown. Here we report that activated NLK suppresses the critical upregulation of mitochondrial biogenesis required in early erythropoiesis. During normal erythropoiesis, mTORC1 facilitates the translational upregulation of Transcription factor A, mitochondrial (TFAM) and Prohibin 2 (PHB2) to increase mitochondrial biogenesis. In our models of DBA, active NLK phosphorylates the regulatory component of mTORC1, thereby suppressing mTORC1 activity and preventing mTORC1-mediated TFAM and PHB2 upregulation and subsequent mitochondrial biogenesis. Improvement of erythropoiesis that accompanies NLK inhibition is negated when TFAM and PHB2 upregulation is prevented. These data demonstrate that a significant contribution of NLK on the pathogenesis of DBA is through loss of mitochondrial biogenesis.

2.
Haematologica ; 108(5): 1222-1231, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36384250

RESUMO

Diamond-Blackfan anemia (DBA) is a ribosomopathy that is characterized by macrocytic anemia, congenital malformations, and early onset during childhood. Genetic studies have demonstrated that most patients carry mutations in one of the 20 related genes, most of which encode ribosomal proteins (RP). Treatment of DBA includes corticosteroid therapy, chronic red blood cell transfusion, and other forms of immunosuppression. Currently, hematopoietic stem cell transplantation is the only cure for DBA. Interestingly, spontaneous remissions occur in 10-20% of transfusion-dependent DBA patients. However, there is no consistent association between specific mutations and clinical manifestations. In the past decades, researchers have made significant progress in understanding the pathogenesis of DBA, but it remains unclear how the ubiquitous RP haploinsufficiency causes the erythroid-specific defect in hematopoiesis in DBA patients, and why there is a difference in penetrance and spontaneous remission among individuals who carry identical mutations. In this paper, we provide a comprehensive review of the development of DBA animal models and discuss the future research directions for these important experimental systems.


Assuntos
Anemia de Diamond-Blackfan , Animais , Anemia de Diamond-Blackfan/genética , Proteínas Ribossômicas/genética , Mutação , Modelos Animais , Hematopoese
3.
Exp Hematol ; 111: 66-78, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35460833

RESUMO

Diamond-Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome that is associated with anemia, congenital anomalies, and cancer predisposition. It is categorized as a ribosomopathy, because more than 80% or patients have haploinsufficiency of either a small or large subunit-associated ribosomal protein (RP). The erythroid pathology is due predominantly to a block and delay in early committed erythropoiesis with reduced megakaryocyte/erythroid progenitors (MEPs). To understand the molecular pathways leading to pathogenesis of DBA, we performed RNA sequencing on mRNA and miRNA from RPS19-deficient human hematopoietic stem and progenitor cells (HSPCs) and compared existing database documenting transcript fluctuations across stages of early normal erythropoiesis. We determined the chromatin regulator, SATB1 was prematurely downregulated through the coordinated action of upregulated miR-34 and miR-30 during differentiation in ribosomal insufficiency. Restoration of SATB1 rescued MEP expansion, leading to a modest improvement in erythroid and megakaryocyte expansion in RPS19 insufficiency. However, SATB1 expression did not affect expansion of committed erythroid progenitors, indicating ribosomal insufficiency affects multiple stages during erythroid differentiation.


Assuntos
Anemia de Diamond-Blackfan , Eritropoese , Proteínas de Ligação à Região de Interação com a Matriz , MicroRNAs , Anemia de Diamond-Blackfan/patologia , Regulação para Baixo , Eritropoese/genética , Células-Tronco Hematopoéticas , Humanos , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Megacariócitos/citologia , MicroRNAs/genética , Proteínas Ribossômicas
4.
Genes (Basel) ; 12(10)2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34681039

RESUMO

Blood cell development is regulated through intrinsic gene regulation and local factors including the microenvironment and cytokines. The differentiation of hematopoietic stem and progenitor cells (HSPCs) into mature erythrocytes is dependent on these cytokines binding to and stimulating their cognate receptors and the signaling cascades they initiate. Many of these pathways include kinases that can diversify signals by phosphorylating multiple substrates and amplify signals by phosphorylating multiple copies of each substrate. Indeed, synthesis of many of these cytokines is regulated by a number of signaling pathways including phosphoinositide 3-kinase (PI3K)-, extracellular signal related kinases (ERK)-, and p38 kinase-dependent pathways. Therefore, kinases act both upstream and downstream of the erythropoiesis-regulating cytokines. While many of the cytokines are well characterized, the nuanced members of the network of kinases responsible for appropriate induction of, and response to, these cytokines remains poorly defined. Here, we will examine the kinase signaling cascades required for erythropoiesis and emphasize the importance, complexity, enormous amount remaining to be characterized, and therapeutic potential that will accompany our comprehensive understanding of the erythroid kinome in both healthy and diseased states.


Assuntos
Diferenciação Celular/genética , Eritrócitos/citologia , Eritropoese/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação da Expressão Gênica/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Fosfatidilinositol 3-Quinases/genética , Fosforilação/genética
5.
J Cell Biol ; 208(2): 197-209, 2015 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-25583996

RESUMO

Signal-dependent sorting of proteins in the early secretory pathway is required for dynamic retention of endoplasmic reticulum (ER) and Golgi components. In this study, we identify the Erv41-Erv46 complex as a new retrograde receptor for retrieval of non-HDEL-bearing ER resident proteins. In cells lacking Erv41-Erv46 function, the ER enzyme glucosidase I (Gls1) was mislocalized and degraded in the vacuole. Biochemical experiments demonstrated that the luminal domain of Gls1 bound to the Erv41-Erv46 complex in a pH-dependent manner. Moreover, in vivo disturbance of the pH gradient across membranes by bafilomycin A1 treatment caused Gls1 mislocalization. Whole cell proteomic analyses of deletion strains using stable isotope labeling by amino acids in culture identified other ER resident proteins that depended on the Erv41-Erv46 complex for efficient localization. Our results support a model in which pH-dependent receptor binding of specific cargo by the Erv41-Erv46 complex in Golgi compartments identifies escaped ER resident proteins for retrieval to the ER in coat protein complex I-formed transport carriers.


Assuntos
Retículo Endoplasmático/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Concentração de Íons de Hidrogênio , Proteínas de Membrana/química , Ligação Proteica , Mapeamento de Interação de Proteínas , Transporte Proteico , Proteólise , Proteínas de Saccharomyces cerevisiae/química , Vacúolos/enzimologia , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
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