Heme Utilization in the Caenorhabditis elegans Hypodermal Cells Is Facilitated by Heme-responsive Gene-2

Chen, Caiyong; Samuel, Tamika K.; Krause, Michael; Dailey, Harry A.; Hamza, Iqbal

doi:10.1074/jbc.m111.307694

Cited by 40 publications

(57 citation statements)

References 54 publications

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“…To measure subcellular heme in various organs within an intact animal, we exploited C. elegans because it is a heme auxotroph. Heme levels can be experimentally manipulated by either nutritional supplementation or genetically regulating the heme trafficking pathways mediated by HRGs (13,14,29,30,57). We generated transgenic worms expressing HRP and APX reporters under the control of tissue-specific promoters.…”

Section: Exogenous and Endogenous Heme Are Trafficked By Distinct Patmentioning

confidence: 99%

“…Although the identity of heme transporters and trafficking factors has seen some headway due to genetic studies in model systems within the past decade (10,13,14,29,30), the lack of proper physical tools to probe heme availability and trafficking at the cell biological level has greatly hindered our progress in understanding the intricacies of cellular and organismal heme homeostasis. To overcome this obstacle, we developed peroxidase-based enzymatic reporters for heme and deployed them in subcellular compartments in mammalian cell lines and in several tissues in the Caenorhabditis elegans animal model.…”

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confidence: 99%

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Regulation of intracellular heme trafficking revealed by subcellular reporters

Yuan

Rietzschel

Kwon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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107

126

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Heme is an essential prosthetic group in proteins that reside in virtually every subcellular compartment performing diverse biological functions. Irrespective of whether heme is synthesized in the mitochondria or imported from the environment, this hydrophobic and potentially toxic metalloporphyrin has to be trafficked across membrane barriers, a concept heretofore poorly understood. Here we show, using subcellular-targeted, genetically encoded hemoprotein peroxidase reporters, that both extracellular and endogenous heme contribute to cellular labile heme and that extracellular heme can be transported and used in toto by hemoproteins in all six subcellular compartments examined. The reporters are robust, show large signal-to-background ratio, and provide sufficient range to detect changes in intracellular labile heme. Restoration of reporter activity by heme is organelle-specific, with the Golgi and endoplasmic reticulum being important sites for both exogenous and endogenous heme trafficking. Expression of peroxidase reporters in Caenorhabditiselegans shows that environmental heme influences labile heme in a tissue-dependent manner; reporter activity in the intestine shows a linear increase compared with muscle or hypodermis, with the lowest heme threshold in neurons. Our results demonstrate that the trafficking pathways for exogenous and endogenous heme are distinct, with intrinsic preference for specific subcellular compartments. We anticipate our results will serve as a heuristic paradigm for more sophisticated studies on heme trafficking in cellular and whole-animal models.

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Section: Exogenous and Endogenous Heme Are Trafficked By Distinct Patmentioning

confidence: 99%

mentioning

confidence: 99%

Regulation of intracellular heme trafficking revealed by subcellular reporters

Yuan

Rietzschel

Kwon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

107

126

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“…Furthermore, proteins responsible for heme traffic across the organelle membranes and for the incorporation of heme into the target hemeproteins are also required. A set works describing inter-and intracellular heme transport systems in C. elegans were recently published (36,42). The complex heme transport system involves functionally different proteins named HRG, initially identified in a screen for genes regulated by heme (43,44).…”

Section: Darkmentioning

confidence: 99%

Silencing of Maternal Heme-binding Protein Causes Embryonic Mitochondrial Dysfunction and Impairs Embryogenesis in the Blood Sucking Insect Rhodnius prolixus

Walter-Nuno

Oliveira

et al. 2013

Journal of Biological Chemistry

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Background: Rhodnius prolixus presents a heme-binding protein (RHBP) in eggs and hemolymph. Results: Eggs lacking RHBP failed to develop embryos and showed defective mitochondria. Conclusion: Maternally provided heme transported by RHBP supports mitochondrial function and early steps of embryogenesis. Significance: Recycling of intercellular transported heme is not restricted to heme auxotroph organisms and may be widespread in metazoans.

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“…The intercellular heme-trafficking protein, HRG-3, is secreted from the intestine and carries heme to developing embryos (Chen et al, 2011). HRG-2 is an extra-intestinal, heme-binding membrane protein that facilitates heme utilization in the worm hypodermis (Chen et al, 2012). How does intestinal heme, derived from the environment, get delivered to hemoproteins in extra-intestinal tissues?…”

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confidence: 99%

Control of Metazoan Heme Homeostasis by a Conserved Multidrug Resistance Protein

et al. 2014

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Several lines of evidence predict that specific pathways must exist in metazoans for the escorted movement of heme, an essential but cytotoxic iron-containing organic ring, within and between cells and tissues, but these pathways remain obscure. In Caenorhabditis elegans, embryonic development is inextricably dependent on both maternally-derived heme and environmentally-acquired heme. Here, we show that the multidrug resistance protein, MRP-5/ABCC5, likely acts as a heme exporter and targeted depletion of mrp-5 in the intestine causes embryonic lethality. Transient knockdown of mrp5 in zebrafish leads to morphological defects and failure to hemoglobinize red blood cells. MRP5 resides on the plasma membrane and endosomal compartments and regulates export of cytosolic heme. Together, our genetic studies in worms, yeast, zebrafish, and mammalian cells identify a conserved, physiological role for a multidrug resistance protein in regulating systemic heme homeostasis. We envision other MRP family members may play similar unanticipated physiological roles in animal development.

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Heme Utilization in the Caenorhabditis elegans Hypodermal Cells Is Facilitated by Heme-responsive Gene-2

Cited by 40 publications

References 54 publications

Regulation of intracellular heme trafficking revealed by subcellular reporters

Regulation of intracellular heme trafficking revealed by subcellular reporters

Silencing of Maternal Heme-binding Protein Causes Embryonic Mitochondrial Dysfunction and Impairs Embryogenesis in the Blood Sucking Insect Rhodnius prolixus

Control of Metazoan Heme Homeostasis by a Conserved Multidrug Resistance Protein

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