caa a22 4500 605542988 CHVBK 20210128100924.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s00109-015-1276-0 doi (NATIONALLICENCE)springer-10.1007/s00109-015-1276-0 Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing [Elektronische Daten] [Reinhard Depping, Wolfgang Jelkmann, Friederike Kosyna] In order to pass through the nuclear pore complex, proteins larger than ∼40kDa 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 ∼100-120kDa 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. Springer-Verlag Berlin Heidelberg, 2015 Hypoxia-inducible factors (HIF) nationallicence Importin nationallicence Nuclear export nationallicence Nuclear import nationallicence HIF prolyl hydroxylases (PHD) nationallicence Depping Reinhard Institute of Physiology, Centre for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany aut Jelkmann Wolfgang Institute of Physiology, Centre for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany aut Kosyna Friederike Institute of Physiology, Centre for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany aut Journal of Molecular Medicine Springer Berlin Heidelberg 93/6(2015-06-01), 599-608 0946-2716 93:6<599 2015 93 109 https://doi.org/10.1007/s00109-015-1276-0 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 review-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00109-015-1276-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Depping Reinhard Institute of Physiology, Centre for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany aut NATIONALLICENCE 700 1- Jelkmann Wolfgang Institute of Physiology, Centre for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany aut NATIONALLICENCE 700 1- Kosyna Friederike Institute of Physiology, Centre for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany aut NATIONALLICENCE 773 0- Journal of Molecular Medicine Springer Berlin Heidelberg 93/6(2015-06-01), 599-608 0946-2716 93:6<599 2015 93 109