Open AccessHypoxia inducible factor 1α regulates T cell receptor signal transduction
Author(s) -
Aaron K. Neumann,
Jaeseok Yang,
Mangat P. Biju,
Suresh K. Joseph,
Randall S. Johnson,
Volker H. Haase,
Bruce D. Freedman,
Laurence A. Turka
Publication year - 2005
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0506070102
Subject(s) - endoplasmic reticulum , signal transduction , microbiology and biotechnology , intracellular , biology , receptor , cytoplasm , phospholipase c , t cell receptor , calcium signaling , cellular adaptation , endocrinology , biochemistry , t cell , immunology , immune system , gene
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) 1α. Here, we have examined the effect of Hif-1α, 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-1α under “normoxic” conditions, we achieved constitutive stabilization of Hif-1α through thymic deletion ofVhlh and reversed Hif-1α stabilization with double deletion ofVhlh andHif-1 α. We found that constitutive activity of Hif-1α resulted in diminished Ca2+ response upon TCR crosslinking despite equivalent activation of phospholipase Cγ1 , normal intracellular Ca2+ stores, and normal entry of Ca2+ across the plasma membrane. Altered Ca2+ response was instead due to accelerated removal of Ca2+ from the cytoplasm into intracellular compartments, which occurred in association with Hif-1α-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-1α, which may be operative at the physiologic oxygen tensions seen in solid lymphoid organs.