Heme oxygenase 1 is expressed in murine erythroid cells where it controls the level of regulatory heme

Abstract

Key Points• Heme oxygenase-1 levels increase during erythroid differentiation.• Heme oxygenase-1 actively participates in maintaining appropriate hemoglobinization rates.Heme is essential for the function of all aerobic cells. However, it can be toxic when it occurs in a non-protein-bound form; cells maintain a fine balance between heme synthesis and catabolism. The only physiological mechanism of heme degradation is by heme oxygenases (HOs). The heme-inducible isoform, HO-1, has been extensively studied in numerous nonerythroid cells, but virtually nothing is known about the expression and potential significance of HO-1 in developing red blood cells. We have demonstrated that HO-1 is present in erythroid cells and that its expression is upregulated during erythroid differentiation. Overexpression of HO-1 in erythroid cells impairs hemoglobin synthesis, whereas HO-1 absence enhances hemoglobinization in cultured erythroid cells. Based on these results, we conclude that HO-1 controls the regulatory heme pool at appropriate levels for any given stage of erythroid differentiation. In summary, our study brings to light the importance of HO-1 expression for erythroid development and expands our knowledge about the fine regulation of hemoglobin synthesis in erythroid cells. Our results indicate that HO-1 plays an important role as a coregulator of the erythroid differentiation process. Moreover, HO-1 expression must be tightly regulated during red blood cell development. (Blood.

The heme exporter Flvcr1 regulates expansion and differentiation of committed erythroid progenitors by controlling intracellular heme accumulation

“…20 HO-1 overexpression in MEL cells impaired hemoglobin synthesis, while fetal liver cells from HO-1 knock-out embryos contained more hemoglobin. We showed that HO-1 is induced in both Flvcr1a-and Flvcr1a/1b-deficient cells and animals.…”

“…1,21,22 Recently, Garcia-Santos et al introduced the concept of a free heme pool also for erythroid cells and demonstrated that HO-1 is involved in its control, thus regulating hemoglobinization. 20 In fact, in erythroid cells, free heme is thought to increase during terminal maturation and control the expression of globin genes. Premature expansion of the regulatory heme pool is expected to result in premature erythroid differentiation while, contrariwise, a contraction of the heme pool should result in inappropriate hemoglobin production.…”

“…Since FLVCR1a and FLVCR1b are heme exporters localized at the plasma membrane and in mitochondria, 9,10 respectively, we hypothesized that their coordinated expression controls the size of the cytosolic free heme pool required for proper erythropoiesis. 20 We tested our hypothesis in K562 cells, in which the expression of FLVCR1a alone or both FLVCR1a and FLVCR1b was down-regulated using specific shRNA. ; Mx-cre mice and Flvcr1a/1b morphants, respectively.…”

BLVRB redox mutation defines heme degradation in a metabolic pathway of enhanced thrombopoiesis in humans

“…25 The BLVRB gene product BV IXb reductase and its structurally distant homolog BLVRA (BV IXa reductase) function downstream of heme oxygenase(s)-1 (inducible HMOX1) and -2 (constitutive HMOX2) within the heme degradation pathway to catalyze reduction of BV IXa (or IXb) tetrapyrrole(s) to the potent antioxidants bilirubin (BR) IXa and IXb. 16,26 We studied expression patterns of the 4 heme degradation pathway genes along erythroid/MK (E/Meg) lineage development using data extracted from platelet 14 and genetic atlases.…”

The ins and outs of erythroid heme transport

“…There is growing evidence that the tight control of intracellular heme levels is accomplished by coordination of heme synthesis, degradation, and trafficking between intracellular compartments. 2 In contrast to the well-characterized biochemistry of heme synthesis and degradation, the mechanisms of heme transport remain somewhat obscure.…”