PMID- 30897319
OWN - NLM
STAT- MEDLINE
DCOM- 20190403
LR  - 20190403
IS  - 1421-9778 (Electronic)
IS  - 1015-8987 (Linking)
VI  - 52
IP  - 3
DP  - 2019
TI  - Moonlighting Protein Glyceraldehyde-3-Phosphate Dehydrogenase: A Cellular 
      Rapid-Response Molecule for Maintenance of Iron Homeostasis in Hypoxia.
PG  - 517-531
LID - 10.33594/000000037 [doi]
AB  - BACKGROUND/AIMS: Hypoxia triggers a rapid increase in iron demand to meet the 
      requirements of enhanced erythropoiesis. The mobilization of iron stores from 
      macrophage to plasma as holo-transferrin (Tf) from where it is accessible to 
      erythroid precursor cells impacts iron homeostasis. Despite the immediate need 
      for enhanced iron uptake by bone marrow cells, numerous studies have shown that 
      transferrin receptor levels do not rise until more than 24 hours after the onset 
      of hypoxia, suggesting the existence of heretofore unknown rapid response 
      cellular machinery for iron acquisition in the early stages of cellular hypoxia. 
      METHODS: We performed flow cytometry to measure cell surface levels of TfR1, 
      GAPDH, and Tf binding after hypoxia treatment. We utilized FRET analysis and 
      co-immunoprecipitation methods to establish the interaction between Tf and GAPDH. 
      RESULTS: In the current study, we demonstrated that hypoxia induces K562 cells to 
      translocate the cytosolic moonlighting protein glyceraldehyde-3-phosphate 
      dehydrogenase (GAPDH) onto cell surfaces and into the extracellular milieu to 
      acquire transferrin-bound iron, even while levels of the classical transferrin 
      receptor TfR1 (CD71) remain suppressed. GAPDH knockdown confirmed this protein's 
      role in transferrin acquisition. Interestingly, macrophages did not show enhanced 
      levels of extracellular GAPDH under hypoxia. CONCLUSION: Our results suggest the 
      role of GAPDH-mediated Tf uptake as a rapid response mechanism by which cells 
      acquire iron during the early stages of hypoxia. This is a tissue-specific 
      phenomenon for the distinct requirements of cells that are consumers of iron 
      versus cells that play a role in iron storage and recycling. This rapid 
      deployment of an abundantly available multipurpose molecule allows hypoxic cells 
      to internalize more Tf and maintain enhanced iron supplies in the early stages of 
      hypoxia before specialized receptors can be synthesized and deployed to the cell 
      membrane.
CI  - (c) Copyright by the Author(s). Published by Cell Physiol Biochem Press.
FAU - Malhotra, Himanshu
AU  - Malhotra H
AD  - Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, India.
FAU - Kumar, Manoj
AU  - Kumar M
AD  - Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, India.
FAU - Chauhan, Anoop Singh
AU  - Chauhan AS
AD  - Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, India.
FAU - Dhiman, Asmita
AU  - Dhiman A
AD  - Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, India.
FAU - Chaudhary, Surbhi
AU  - Chaudhary S
AD  - Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, India.
FAU - Patidar, Anil
AU  - Patidar A
AD  - Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, India.
FAU - Jaiswal, Pallavi
AU  - Jaiswal P
AD  - Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, India.
FAU - Sharma, Kapil
AU  - Sharma K
AD  - Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, India.
FAU - Sheokand, Navdeep
AU  - Sheokand N
AD  - Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, India.
FAU - Raje, Chaaya Iyengar
AU  - Raje CI
AD  - National Institute of Pharmaceutical Education & Research, Punjab, India.
FAU - Raje, Manoj
AU  - Raje M
AD  - Institute of Microbial Technology, CSIR, Sector 39A, Chandigarh, India, 
      manoj@imtech.res.in.
LA  - eng
GR  - Department of Biotechnology, Ministry of Science and Technology/India
GR  - Council of Scientific and Industrial Research/India
GR  - University Grants Commission/India
PT  - Journal Article
PL  - Germany
TA  - Cell Physiol Biochem
JT  - Cellular physiology and biochemistry : international journal of experimental 
      cellular physiology, biochemistry, and pharmacology
JID - 9113221
RN  - 0 (Antigens, CD)
RN  - 0 (CD71 antigen)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, Transferrin)
RN  - 0 (Transferrin)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.2.1.- (Glyceraldehyde-3-Phosphate Dehydrogenases)
SB  - IM
MH  - Antigens, CD/genetics/metabolism
MH  - *Cell Hypoxia
MH  - Cell Membrane/metabolism
MH  - Cytosol/metabolism
MH  - Glyceraldehyde-3-Phosphate Dehydrogenases/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Humans
MH  - Iron/*metabolism
MH  - K562 Cells
MH  - Macrophages/cytology/metabolism
MH  - Protein Binding
MH  - RNA Interference
MH  - RNA, Small Interfering/metabolism
MH  - Receptors, Transferrin/genetics/metabolism
MH  - Transferrin/metabolism
OTO - NOTNLM
OT  - GAPDH
OT  - Hypoxia
OT  - Iron
OT  - Rapid response
COIS- The authors have no conflicts of interest to report.
EDAT- 2019/03/22 06:00
MHDA- 2019/04/04 06:00
CRDT- 2019/03/22 06:00
PHST- 2018/05/24 00:00 [received]
PHST- 2019/03/18 00:00 [accepted]
PHST- 2019/03/22 06:00 [entrez]
PHST- 2019/03/22 06:00 [pubmed]
PHST- 2019/04/04 06:00 [medline]
AID - 10.33594/000000037 [doi]
PST - ppublish
SO  - Cell Physiol Biochem. 2019;52(3):517-531. doi: 10.33594/000000037.