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

In order to pass through the nuclear pore complex, proteins larger than similar to 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 O-2 deficiency is controlled by hypoxia-inducible factors (HIFs). These are heterodimeric transcription factors of each similar to 100-120 kDa proteins, consisting of one out of three different O-2-labile alpha subunits (primarily HIF-1 alpha) and a more constitutive 1 beta subunit. In the presence of O-2, the alpha 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-1 alpha and HIF-1 beta is mainly mediated by importins alpha and beta (alpha/beta). HIF-1 alpha can shuttle between nucleus and cytoplasm, while HIF-1 beta 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 alpha/beta receptors. PHD2 shows an atypical NLS, and its nuclear import does not occur via the classical pathway. PHD2-mediated hydroxylation of HIF-1 alpha 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 alpha/beta 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.