Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins

Haem homeostasis: Role of HRG-1 proteins The three-dimensional structures of haemoglobin and scores of other haem-containing proteins have been determined and the biosynthesis of haem has been thoroughly studied. But little is known about what happens to haems within the cell. The roundworm C. elega...

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Veröffentlicht in:Nature 2008-06, Vol.453 (7198), p.1127-1131
Hauptverfasser: Rajagopal, Abbhirami, Rao, Anita U., Amigo, Julio, Tian, Meng, Upadhyay, Sanjeev K., Hall, Caitlin, Uhm, Suji, Mathew, M. K., Fleming, Mark D., Paw, Barry H., Krause, Michael, Hamza, Iqbal
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Zusammenfassung:Haem homeostasis: Role of HRG-1 proteins The three-dimensional structures of haemoglobin and scores of other haem-containing proteins have been determined and the biosynthesis of haem has been thoroughly studied. But little is known about what happens to haems within the cell. The roundworm C. elegans can help fill this gap: it is a haem auxotroph, which means that although it needs haem for its haemoproteins, it can't synthesize it so scavenges its supplies from its surroundings. Exploiting the worm's well defined genetics and with no endogenous haem to complicate matters, Rajagopal et al . identified HRG-1 and HRG-4, previously unknown transmembrane proteins, as essential to haem utilization. These proteins are broadly conserved in animals and in humans: for instance, zebrafish with lowered levels of HRG-1 show anaemia, and severe depletion of HRG-1 causes congenital malformations as other haem proteins crucial for development are also affected. The discovery of this haem transport mechanism may provide insights into human disorders — as well as possible drug targets for new anthelmintics to fight worm infestations. Caenorhabditis elegans (which haeme auxotrophs), are used to identify the proteins involved in haeme homeostasis. It is shown that the proteins of HRG-1 and its paralogue HRG-4 are essential for haeme homeostasis, as they are novel transmembrane proteins residing in an intracellular department. Transient knockdown of hrg-1 in zebrafish led to hydrocephalus, yolk tube abnormalities, and defects in erythropoesis. The human and worm HRG proteins co-localize, and bind and transport haeme, showing there is evolutionary conservation of its function. Haems are metalloporphyrins that serve as prosthetic groups for various biological processes including respiration, gas sensing, xenobiotic detoxification, cell differentiation, circadian clock control, metabolic reprogramming and microRNA processing 1 , 2 , 3 , 4 . With a few exceptions, haem is synthesized by a multistep biosynthetic pathway comprising defined intermediates that are highly conserved throughout evolution 5 . Despite our extensive knowledge of haem biosynthesis and degradation, the cellular pathways and molecules that mediate intracellular haem trafficking are unknown. The experimental setback in identifying haem trafficking pathways has been the inability to dissociate the highly regulated cellular synthesis and degradation of haem from intracellular trafficking events 6 . Caenorhabdit
ISSN:0028-0836
1476-4687
1476-4679
DOI:10.1038/nature06934