PMID- 20581113
OWN - NLM
STAT- MEDLINE
DCOM- 20100917
LR  - 20231105
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 35
DP  - 2010 Aug 27
TI  - Toxoplasma gondii activates hypoxia-inducible factor (HIF) by stabilizing the 
      HIF-1alpha subunit via type I activin-like receptor kinase receptor signaling.
PG  - 26852-26860
LID - S0021-9258(20)59477-5 [pii]
LID - 10.1074/jbc.M110.147041 [doi]
AB  - Toxoplasma gondii is an intracellular protozoan parasite that can cause 
      devastating disease in fetuses and immune-compromised individuals. We previously 
      reported that the alpha subunit of the host cell transcription factor, 
      hypoxia-inducible factor-1 (HIF-1), is up-regulated by infection and necessary 
      for Toxoplasma growth. Under basal conditions, HIF-1alpha is constitutively 
      expressed but rapidly targeted for proteasomal degradation after two proline 
      residues are hydroxylated by a family of prolyl hydroxylases (PHDs). The PHDs are 
      alpha-ketoglutarate-dependent dioxygenases that have low K(m) values for oxygen, 
      making them important cellular oxygen sensors. Thus, when oxygen levels decrease, 
      HIF-1alpha is not hydroxylated, and HIF-1 is activated. How Toxoplasma activates 
      HIF-1 under normoxic conditions remains unknown. Here, we report that Toxoplasma 
      infection increases HIF-1alpha stability by preventing HIF-1alpha prolyl 
      hydroxylation. Infection significantly decreases PHD2 abundance, which is the key 
      prolyl hydroxylase for regulating HIF-1alpha. The effects of Toxoplasma on 
      HIF-1alpha abundance and prolyl hydroxylase activity require activin-like 
      receptor kinase signaling. Finally, parasite growth is severely diminished when 
      signaling from this family of receptors is inhibited. Together, these data 
      indicate that PHD2 is a key host cell factor for T. gondii growth and represent a 
      novel mechanism by which a microbial pathogen subverts host cell signaling and 
      transcription to establish its replicative niche.
FAU - Wiley, Mandi
AU  - Wiley M
AD  - Department of Microbiology and Immunology, University of Oklahoma Health Sciences 
      Center, Oklahoma City, Oklahoma 73104.
FAU - Sweeney, Kristin R
AU  - Sweeney KR
AD  - Department of Microbiology and Immunology, University of Oklahoma Health Sciences 
      Center, Oklahoma City, Oklahoma 73104.
FAU - Chan, Denise A
AU  - Chan DA
AD  - Department of Radiation Oncology, University of California, San Francisco, 
      California 94143; Department of Radiation Oncology, Stanford University School of 
      Medicine, Stanford, California 94305.
FAU - Brown, Kevin M
AU  - Brown KM
AD  - Department of Microbiology and Immunology, University of Oklahoma Health Sciences 
      Center, Oklahoma City, Oklahoma 73104.
FAU - McMurtrey, Curtis
AU  - McMurtrey C
AD  - Department of Microbiology and Immunology, University of Oklahoma Health Sciences 
      Center, Oklahoma City, Oklahoma 73104.
FAU - Howard, Eric W
AU  - Howard EW
AD  - Department of Cell Biology, University of Oklahoma Health Sciences Center, 
      Oklahoma City, Oklahoma 73104.
FAU - Giaccia, Amato J
AU  - Giaccia AJ
AD  - Department of Radiation Oncology, University of California, San Francisco, 
      California 94143.
FAU - Blader, Ira J
AU  - Blader IJ
AD  - Department of Microbiology and Immunology, University of Oklahoma Health Sciences 
      Center, Oklahoma City, Oklahoma 73104.
LA  - eng
GR  - R01 AI069986/AI/NIAID NIH HHS/United States
GR  - AI069986/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100625
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - EC 1.14.11.2 (EGLN1 protein, human)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
RN  - EC 2.7.11.30 (Activin Receptors, Type I)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Activin Receptors, Type I/*metabolism
MH  - Animals
MH  - HeLa Cells
MH  - Humans
MH  - Hydroxylation
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases
MH  - Oxygen/metabolism
MH  - Procollagen-Proline Dioxygenase/*metabolism
MH  - Proteasome Endopeptidase Complex/metabolism
MH  - Protein Stability
MH  - Toxoplasma/*metabolism
MH  - Toxoplasmosis/*mortality
PMC - PMC2930684
EDAT- 2010/06/29 06:00
MHDA- 2010/09/21 06:00
PMCR- 2011/08/27
CRDT- 2010/06/29 06:00
PHST- 2010/06/29 06:00 [entrez]
PHST- 2010/06/29 06:00 [pubmed]
PHST- 2010/09/21 06:00 [medline]
PHST- 2011/08/27 00:00 [pmc-release]
AID - S0021-9258(20)59477-5 [pii]
AID - M110.147041 [pii]
AID - 10.1074/jbc.M110.147041 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Aug 27;285(35):26852-26860. doi: 10.1074/jbc.M110.147041. Epub 
      2010 Jun 25.