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Regulation of intracellular heme trafficking revealed by subcellular reporters

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conference contribution
posted on 25.08.2017, 10:22 by Xiaojing Yuan, Nicole Rietzschel, Hanna Kwon, Ana Beatriz Walter Nuno, David A. Hanna, John D. Phillips, Emma L. Raven, Amit R. Reddi, Iqbal Hamza
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 Caenorhabditis elegans 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.

History

Citation

Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (35), pp. E5144-E5152

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Molecular & Cell Biology

Version

AM (Accepted Manuscript)

Published in

Proceedings of the National Academy of Sciences of the United States of America

Publisher

National Academy of Sciences

issn

0027-8424

eissn

1091-6490

Acceptance date

11/07/2016

Copyright date

2016

Available date

25/08/2017

Publisher version

http://www.pnas.org/content/113/35/E5144

Notes

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1609865113/-/DCSupplemental.

Language

en

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