8 The proliferation and differentiation of subsequent erythroid progenitors including late stage BFU-E and colony forming unit-erythroid (CFU-E) cells occur after the stimulation by erythropoietin (EPO), a glycoprotein cytokine secreted by the kidneys. For example, glucocorticoids regulate both the proliferation and differentiation of early erythroid progenitors known as early burst forming unit-erythroid (BFU-E) cells. 6 During erythropoiesis, these progenitors undergo a red cell lineage specific terminal differentiation program to generate mature erythrocytes.Įrythrocyte production is tightly regulated by a set of hormones. About two million new erythrocytes per second are generated in adult humans 7 via proliferation and differentiation of a self-renewing population of pluripotent hematopoietic stem cells (HSC) located in the yolk sac, liver, spleen (antenatal) or bone marrow (postnatal) that give rise to early erythroid progenitors. 6 These cells, therefore, must be continuously and rapidly replaced in vertebrates. Erythrocytes have a finite lifespan (approximately 120 days in humans) in the circulatory system before they are recycled mainly in the spleen by macrophages. This cell differentiation event leads to the generation of highly specialized erythrocytes that function as dedicated oxygen and carbon dioxide transporting cells across the body. Formation of red blood cellsĮrythropoiesis is a vital process throughout vertebrate life, which helps maintain adequate tissue oxygenation under physiological and nonphysiological states ( e.g., hypoxia, hemorrhage or other anemic conditions). Hence, the dysfunction of this chaperone system is invariably associated with ineffective erythropoiesis, which leads to chronic anemia in several hematological diseases in humans. These multifaceted roles of the Hsp70 chaperone include maintaining erythroid progenitors, assessing fitness of progenitors prior to initiating lineage specific terminal cell differentiation, supporting hemoglobin (Hb) biogenesis, counteracting proteotoxicities and preventing premature apoptosis of differentiating erythroblasts, and promoting viability of terminally differentiated erythrocytes via protein repair. In particular, the heat shock protein 70 (Hsp70) chaperone system is maintained at high levels during red blood cell differentiation.3-5 Emerging data demonstrate that Hsp70 machineries have distinct functions ranging from modulating cell signaling to PQC activities at different stages of erythropoiesis. Under such challenging conditions, molecular chaperones that constitute an essential part of cellular protein quality control (PQC) pathways, help maintain proteostasis by decreasing protein misfolding and aggregation, and promote cell viability.1,2 In response to cell differentiation, considerable rearrangements in cellular chaperomes have been detected,2,3 but the functional consequences of such changes largely remain enigmatic. IntroductionĬells are highly vulnerable to proteotoxic stresses during widespread remodeling of proteomes that typically accompany cell differentiation. The work also discusses the modulatory roles of this chaperone system in a wide range of hematological diseases and the therapeutic gain of targeting Hsp70. We present new insights into the protein repair-only function(s) of the Hsp70 system, perhaps to minimize protein degradation in mature erythrocytes to warrant their optimal function and survival in the vasculature under healthy conditions. In this review, we present latest advances in our understanding of the distinct functions of this chaperone system in differentiating erythroblasts and terminally differentiated mature erythrocytes. Recent findings show that abnormalities in the expression, localization and function of the members of this chaperone system are linked to ineffective erythropoiesis in multiple hematological diseases in humans. The heat shock protein 70 (Hsp70) molecular chaperone system supports a plethora of functions that help maintain cellular protein homeostasis (proteostasis) and promote red blood cell differentiation and survival. Such cytotoxic conditions could prevent proper cell differentiation resulting in premature apoptosis of erythroblasts (ineffective erythropoiesis). Extensive reorganization and depletion of the erythroblast proteome leading to the deterioration of general cellular protein quality control pathways and rapid hemoglobin biogenesis rates could generate misfolded/aggregated proteins and trigger proteotoxic stresses during erythropoiesis. Erythropoiesis is a tightly regulated cell differentiation process in which specialized oxygen- and carbon dioxide-carrying red blood cells are generated in vertebrates.
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