Secreted glyceraldehye-3-phosphate dehydrogenase is a multifunctional autocrine transferrin receptor for cellular iron acquisition

Sheokand, Navdeep, Kumar, Santosh, Malhotra, Himanshu, Tillu, Vikas, Raje, Chaaya Iyengar and Raje, Manoj (2013) Secreted glyceraldehye-3-phosphate dehydrogenase is a multifunctional autocrine transferrin receptor for cellular iron acquisition. BBA - General Subjects , 1830 6: 3816-3827. doi:10.1016/j.bbagen.2013.03.019


Author Sheokand, Navdeep
Kumar, Santosh
Malhotra, Himanshu
Tillu, Vikas
Raje, Chaaya Iyengar
Raje, Manoj
Title Secreted glyceraldehye-3-phosphate dehydrogenase is a multifunctional autocrine transferrin receptor for cellular iron acquisition
Journal name BBA - General Subjects    Check publisher's open access policy
ISSN 0304-4165
1872-8006
Publication date 2013-06-01
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.bbagen.2013.03.019
Open Access Status Not yet assessed
Volume 1830
Issue 6
Start page 3816
End page 3827
Total pages 12
Place of publication Amsterdam, Netherlands
Publisher Elsevier BV
Language eng
Formatted abstract
Background: The long held view is that mammalian cells obtain transferrin (Tf) bound iron utilizing specialized membrane anchored receptors. Here we report that, during increased iron demand, cells secrete the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) which enhances cellular uptake of Tf and iron.

Methods: These observations could be mimicked by utilizing purified GAPDH injected into mice as well as when supplemented in culture medium of model cell lines and primary cell types that play a key role in iron metabolism. Transferrin and iron delivery was evaluated by biochemical, biophysical and imaging based assays.

Results: This mode of iron uptake is a saturable, energy dependent pathway, utilizing raft as well as non-raft domains of the cell membrane and also involves the membrane protein CD87 (uPAR). Tf internalized by this mode is also catabolized.

Conclusions: Our research demonstrates that, even in cell types that express the known surface receptor based mechanism for transferrin uptake, more transferrin is delivered by this route which represents a hidden dimension of iron homeostasis.

General significance: Iron is an essential trace metal for practically all living organisms however its acquisition presents major challenges. The current paradigm is that living organisms have developed well orchestrated and evolved mechanisms involving iron carrier molecules and their specific receptors to regulate its absorption, transport, storage and mobilization. Our research uncovers a hidden and primitive pathway of bulk iron trafficking involving a secreted receptor that is a multifunctional glycolytic enzyme that has implications in pathological conditions such as infectious diseases and cancer.
Keyword Glyceraldehyde-3-phosphate dehydrogenase
Iron
Multifunctional protein
Trafficking
Transferrin receptor
Urokinase plasminogen activator receptor
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 12 times in Thomson Reuters Web of Science Article | Citations
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