title: Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing.
abstract: In order to pass through the nuclear pore complex, proteins larger than ∼40 kDa require specific nuclear transport receptors. Defects in nuclear-cytoplasmatic transport affect fundamental processes such as development, inflammation and oxygen sensing. The transcriptional response to O2 deficiency is controlled by hypoxia-inducible factors (HIFs). These are heterodimeric transcription factors of each ∼100-120 kDa proteins, consisting of one out of three different O2-labile α subunits (primarily HIF-1α) and a more constitutive 1β subunit. In the presence of O2, the α subunits are hydroxylated by specific prolyl-4-hydroxylase domain proteins (PHD1, PHD2, and PHD3) and an asparaginyl hydroxylase (factor inhibiting HIF-1, FIH-1). The prolyl hydroxylation causes recognition by von Hippel-Lindau tumor suppressor protein (pVHL), ubiquitination, and proteasomal degradation. The activity of the oxygen sensing machinery depends on dynamic intracellular trafficking. Nuclear import of HIF-1α and HIF-1β is mainly mediated by importins α and β (α/β). HIF-1α can shuttle between nucleus and cytoplasm, while HIF-1β is permanently inside the nucleus. pVHL is localized to both compartments. Nuclear import of PHD1 relies on a nuclear localization signal (NLS) and uses the classical import pathway involving importin α/β receptors. PHD2 shows an atypical NLS, and its nuclear import does not occur via the classical pathway. PHD2-mediated hydroxylation of HIF-1α occurs predominantly in the cell nucleus. Nuclear export of PHD2 involves a nuclear export signal (NES) in the N-terminus and depends on the export receptor chromosome region maintenance 1 (CRM1). Nuclear import of PHD3 is mediated by importin α/β receptors and depends on a non-classical NLS. Specific modification of the nuclear translocation of the three PHD isoforms could provide a promising strategy for the development of new therapeutic substances to tackle major diseases.
authors: Institute of Physiology, Centre for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany, Depping@physio.uni-luebeck.de.
authors: Reinhard
authors: R
authors: Depping
authors: Wolfgang
authors: W
authors: Jelkmann
authors: Friederike Katharina
authors: FK
authors: Kosyna
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D015687:Cell Hypoxia; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism; D028884:Karyopherins / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: D051793:Hypoxia-Inducible Factor 1; D028884:Karyopherins; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010100:Oxygen