title: Prolyl hydroxylase PHD3 activates oxygen-dependent protein aggregation.
abstract: The HIF prolyl hydroxylases (PHDs/EGLNs) are central regulators of the molecular responses to oxygen availability. One isoform, PHD3, is expressed in response to hypoxia and causes apoptosis in oxygenated conditions in neural cells. Here we show that PHD3 forms subcellular aggregates in an oxygen-dependent manner. The aggregation of PHD3 was seen under normoxia and was strongly reduced under hypoxia or by the inactivation of the PHD3 hydroxylase activity. The PHD3 aggregates were dependent on microtubular integrity and contained components of the 26S proteasome, chaperones, and ubiquitin, thus demonstrating features that are characteristic for aggresome-like structures. Forced expression of the active PHD3 induced the aggregation of proteasomal components and activated apoptosis under normoxia in HeLa cells. The apoptosis was seen in cells prone to PHD3 aggregation and the PHD3 aggregation preceded apoptosis. The data demonstrates the cellular oxygen sensor PHD3 as a regulator of protein aggregation in response to varying oxygen availability.
authors.affiliation: Turku Centre for Biotechnology, Turku University and Abo Akademi University, FIN-29521 Turku, Finland.
authors.forename: Krista
authors.initials: K
authors.lastname: Rantanen
authors.forename: Juha
authors.initials: J
authors.lastname: Pursiheimo
authors.forename: Heidi
authors.initials: H
authors.lastname: Högel
authors.forename: Virpi
authors.initials: V
authors.lastname: Himanen
authors.forename: Eric
authors.initials: E
authors.lastname: Metzen
authors.forename: Panu M
authors.initials: PM
authors.lastname: Jaakkola
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D010100:Oxygen / Q000494:pharmacology*; D011393:Procollagen-Proline Dioxygenase / Q000737:chemistry* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020836:Protein Structure, Quaternary; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology
chemical_list: D011393:Procollagen-Proline Dioxygenase; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen