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Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing

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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.

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Acknowledgments

The authors gratefully acknowledge financial support by the “Werner and Klara Kreitz-Stiftung” and the “Sektion Medizin an der Universität zu Lübeck J19-2015”. The authors wish to thank G. Fletschinger for preparing the artwork.

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  1. Institute of Physiology, Centre for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany

    Reinhard Depping, Wolfgang Jelkmann & Friederike Katharina Kosyna

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  1. Reinhard Depping
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  2. Wolfgang Jelkmann
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  3. Friederike Katharina Kosyna
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Correspondence to Reinhard Depping.

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Depping, R., Jelkmann, W. & Kosyna, F.K. Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing. J Mol Med 93, 599–608 (2015). https://doi.org/10.1007/s00109-015-1276-0

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  • DOI: https://doi.org/10.1007/s00109-015-1276-0

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