Protein biogenesis at the endoplasmic reticulum (ER) in eukaryotic cells is monitored by a protein quality control system named ERassociated protein degradation (ERAD). While there has been substantial progress in understanding how ERAD eliminates defective polypeptides generated from erroneous folding, how cells remove nascent chains stalled in the translocon during co-translational protein insertion into the ER is unclear. Here we show that ribosome stalling during protein translocation induces the attachment of UFM1, a ubiquitin-like modifier, to two conserved lysine residues near the COOH-terminus of the 60S ribosomal subunit RPL26 (uL24) at the ER. Strikingly, RPL26 UFMylation enables the degradation of stalled nascent chains, but unlike ERAD or previously established cytosolic ribosome-associated quality control (RQC), which uses proteasome to degrade their client proteins, ribosome UFMylation promotes the targeting of a translocation-arrested ER protein to lysosomes for degradation. RPL26 UFMylation is upregulated during erythroid differentiation to cope with increased secretory flow, and compromising UFMylation impairs protein secretion, and ultimately hemoglobin production. We propose that in metazoan, co-translational protein translocation into the ER is safeguarded by a UFMylation-dependent protein quality control mechanism, which when impaired causes anemia in mice and abnormal neuronal development in humans.
Erythropoietin (EPO) has shown beneficial effects in the regulation of obesity and metabolic syndrome; however, the detailed mechanism is still largely unknown. Here, we created mice with adipocyte-specific deletion of EPO receptor. These mice exhibited obesity and decreased glucose tolerance and insulin sensitivity, especially when fed a high-fat diet. Moreover, EPO increased oxidative metabolism, fatty acid oxidation, and key metabolic genes in adipocytes and in white adipose tissue from diet-induced obese wild-type mice. Increased metabolic activity by EPO is associated with induction of brown fat–like features in white adipocytes, as demonstrated by increases in brown fat gene expression, mitochondrial content, and uncoupled respiration. Peroxisome proliferator–activated receptor (PPAR)α was found to mediate EPO activity because a PPARα antagonist impaired EPO-mediated induction of brown fat–like gene expression and uncoupled respiration. PPARα also cooperates with Sirt1 activated by EPO through modulating the NAD+ level to regulate metabolic activity. PPARα targets, including PPARγ coactivator 1α, uncoupling protein 1, and carnitine palmitoyltransferase 1α, were increased by EPO but impaired by Sirt1 knockdown. Sirt1 knockdown also attenuated adipose response to EPO. Collectively, EPO, as a novel regulator of adipose energy homeostasis via these metabolism coregulators, provides a potential therapeutic strategy to protect against obesity and metabolic disorders.
Erythropoietin (EPO) regulation of red blood cell production and its induction at reduced oxygen tension provides for the important erythropoietic response to ischemic stress. The cloning and production of recombinant human EPO has led to its clinical use in patients with anemia for two and half decades and has facilitated studies of EPO action. Reports of animal and cell models of ischemic stress in vitro and injury suggest potential EPO benefit beyond red blood cell production including vascular endothelial response to increase nitric oxide production, which facilitates oxygen delivery to brain, heart and other non-hematopoietic tissues. This review discusses these and other reports of EPO action beyond red blood cell production, including EPO response affecting metabolism and obesity in animal models. Observations of EPO activity in cell and animal model systems, including mice with tissue specific deletion of EPO receptor (EpoR), suggest the potential for EPO response in metabolism and disease.
Special AT-rich binding protein 1 (SATB1) nuclear protein, expressed predominantly in T cells, regulates genes through targeting chromatin remodeling during T-cell maturation. Here we show SATB1 family protein induction during early human adult erythroid progenitor cell differentiation concomitant with ⑀-globin expression. Erythroid differentiation of human erythroleukemia K562 cells by hemin simultaneously increases ␥-globin and down-regulates SATB1 family protein and ⑀-globin gene expression. Chromatin immunoprecipitation using anti-SATB1 antibody shows selective binding in vivo in the -globin cluster to the hypersensitive site 2 (HS2) in the locus control region (LCR) and to the ⑀-globin promoter. SATB1 overexpression increases ⑀-globin and decreases ␥-globin gene expression accompanied by histone hyperacetylation and hypomethylation in chromatin from the ⑀-globin promoter and HS2, and histone hypoacetylation and hypermethylation associated with the ␥-globin promoter. In K562 cells SATB1 family protein forms a complex with CREB-binding protein ( IntroductionThe human -globin gene cluster on chromosome 11 consists of 5 developmentally specific genes for embryonic (⑀), fetal ( G ␥, A ␥), and adult (␦, ) globins. A strong enhancer, located in the far upstream region of the cluster called the locus control region (LCR), contains 5 DNase I hypersensitive (HS) sites and is able to enhance tissue-specific globin gene expression and provide a high level of transcription activity from human globin gene constructs in transgenic mice. Transcription factors such as erythroid Krüppel-like factor (EKLF), GATA-1, and NF-E2, that bind to the LCR and other regulatory elements, and promoters in the globin gene locus, have been reported to regulate chromatin histone acetylation by associating with histone acetyltransferases. [1][2][3] The LCR is required to increase the rate of transcription but may be dispensable for formation of an open chromatin domain of a downstream active globin gene in erythroid cells. 4,5 For globin gene expression, spatial organization of the -globin cluster requires special interactions between distal transcriptional elements in the LCR and downstream active globin genes. Some developmental specificity between individual hypersensitive sites in the LCR and downstream globin genes is evident such as the interaction between HS2 and ⑀-globin for transcription activation. 6 Complex packaging of eukaryotic chromosomes in nuclei creates chromatin loops and matrix/scaffold attachment regions (MARs/SARs; the term MARs is used here), originally identified as gDNA fragments that remain tightly associated with saltextracted and DNase I-digested nuclei, have been postulated to be localized at the base of chromatin loops. 7 MARs identified by such criteria often contain a base-unpairing region (BUR), the DNA bases of which become continuously unpaired when subjected to negative superhelical strain. 8,9 Many candidate MARs in the -globin cluster appear to be in regions of mass binding sites for transcription ...
Since the isolation and purification of erythropoietin (EPO) in 1977, the essential role of EPO for mature red blood cell production has been well established. The cloning and production of recombinant human EPO led to its widespread use in treating patients with anaemia. However, the biological activity of EPO is not restricted to regulation of erythropoiesis. EPO receptor (EPOR) expression is also found in endothelial, brain, cardiovascular and other tissues, although at levels considerably lower than that of erythroid progenitor cells. This review discusses the survival and proliferative activity of EPO that extends beyond erythroid progenitor cells. Loss of EpoR expression in mouse models provides evidence for the role of endogenous EPO signalling in nonhaematopoietic tissue during development or for tissue maintenance and/or repair. Determining the extent and distribution of receptor expression provides insights into the potential protective activity of erythropoietin in brain, heart and other nonhaematopoietic tissues.
Hypoxia can induce erythropoiesis through regulated increase of erythropoietin (Epo) production. We investigated the direct influence of oxygen tension (pO 2 ) in the physiologic range (2-8%) on erythroid progenitor cell differentiation using cultures of adult human hematopoietic progenitor cells exposed to decreasing (20 -2%) pO 2 and independent of variation in Epo levels. Decreases in Hbcontaining cells were observed at the end of the culture period with decreasing pO 2 . This is due in part to a reduction in cell growth, and at 2% O 2 a marked increase in cell toxicity. Analysis of the kinetics of cell differentiation showed an increase in the proportion of cells with glycophorin A expression and Hb accumulation at physiologic pO 2 . The cells were characterized by an early induction of γ-globin expression and a delay and reduction in peak levels of β-globin expression. Overall, fetal Hb and γ-globin expression were increased at physiologic pO 2 but the increases were reduced at 2% O 2 as cultures become cytotoxic. At reduced pO 2 , induction of EPO-receptor (EPO-R) by Epo was decreased and delayed, analogous to the delay in β-globin induction. The oxygen dependent reduction of EPO-R can account for the associated cytotoxicity at 2% O 2 . Epo induction of erythroid transcription factors, EKLF, GATA-1 and SCL/Tal-1, was also delayed and decreased at reduced pO 2 , consistent with lower levels of EPO-R and resultant Epo signaling. These changes in EPO-R and globin gene expression raise the possibility that the early increase of γ-globin is a consequence of reduced Epo signaling and a delay in induction of erythroid transcription factors.
Erythropoietin activity, required for erythropoiesis, is not restricted to the erythroid lineage. In light of reports on the metabolic effects of erythropoietin, we examined the effect of erythropoietin signaling on skeletal muscle fiber type development. Skeletal muscles that are rich in slow twitch fibers are associated with increased mitochondrial oxidative activity and corresponding expression of related genes compared to muscle rich in fast twitch fibers. Although erythropoietin receptor is expressed on muscle progenitor/precursor cells and is down regulated in mature muscle fibers, we found that skeletal muscles from mice with high erythropoietin production in vivo exhibit an increase in the proportion of slow twitch myofibers and increased mitochondrial activity. In comparison, skeletal muscle from wild type mice and mice with erythropoietin activity restricted to erythroid tissue have fewer slow twitch myofibers and reduced mitochondrial activity. PGC-1α activates mitochondrial oxidative metabolism and converts the fast myofibers to slow myofibers when overexpressed in skeletal muscle and PGC- 1α was elevated by 2-fold in mice with high erythropoietin. In vitro erythropoietin treatment of primary skeletal myoblasts increased mitochondrial biogenesis gene expression including PGC- 1α by 2.6-fold, CytC by 2-fold, oxygen consumption rate by 2-fold, and citrate synthase activity by 58%. Erythropoietin also increases AMPK, which induces PGC-1α and stimulates slow oxidative fiber formation. These data suggest that erythropoietin contributes to skeletal muscle fiber programming and metabolism, and increases PGC-1α and AMPK activity during muscle development directly to affect the proportion of slow/fast twitch myofibers in mature skeletal muscle.
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