Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction.
Low oxygen pressures exist in many solid tissues, including primary and secondary lymphoid organs. One key element in cellular adaptation to hypoxia is induced expression of hypoxia inducible factor (Hif) 1alpha. Here, we have examined the effect of Hif-1alpha, isolated from the myriad other effects of hypoxia, on T cell receptor (TCR) signaling in thymocytes. Because pVHL (von Hippel-Lindau protein) directs the proteolysis of Hif-1alpha under "normoxic" conditions, we achieved constitutive stabilization of Hif-1alpha through thymic deletion of Vhlh and reversed Hif-1alpha stabilization with double deletion of Vhlh and Hif-1alpha. We found that constitutive activity of Hif-1alpha resulted in diminished Ca(2+) response upon TCR crosslinking despite equivalent activation of phospholipase C(gamma1), normal intracellular Ca(2+) stores, and normal entry of Ca(2+) across the plasma membrane. Altered Ca(2+) response was instead due to accelerated removal of Ca(2+) from the cytoplasm into intracellular compartments, which occurred in association with Hif-1alpha-dependent overexpression of the calcium pump SERCA2 (sarcoplasmic/endoplasmic reticulum calcium ATPase 2). These data suggest a unique mechanism for control of TCR signaling through Hif-1alpha, which may be operative at the physiologic oxygen tensions seen in solid lymphoid organs.
Neumann
Aaron K
AK
Department of Medicine and Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
Yang
Jaeseok
J
Biju
Mangat P
MP
Joseph
Suresh K
SK
Johnson
Randall S
RS
Haase
Volker H
VH
Freedman
Bruce D
BD
Turka
Laurence A
LA
D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011948:Receptors, Antigen, T-Cell; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C494469:VHL protein, mouse; C506947:Atp2a2 protein, mouse; D000252:Calcium-Transporting ATPases