title: The putative RNA helicase HELZ promotes cell proliferation, translation initiation and ribosomal protein S6 phosphorylation.
abstract: The hypoxia-inducible transcription factor (HIF) is a key component of the cellular adaptation mechanisms to hypoxic conditions. HIFα subunits are degraded by prolyl-4-hydroxylase domain (PHD) enzyme-dependent prolyl-4-hydroxylation of LxxLAP motifs that confer oxygen-dependent proteolytic degradation. Interestingly, only three non-HIFα proteins contain two conserved LxxLAP motifs, including the putative RNA helicase with a zinc finger domain HELZ. However, HELZ proteolytic regulation was found to be oxygen-independent, supporting the notion that a LxxLAP sequence motif alone is not sufficient for oxygen-dependent protein destruction. Since biochemical pathways involving RNA often require RNA helicases to modulate RNA structure and activity, we used luciferase reporter gene constructs and metabolic labeling to demonstrate that HELZ overexpression activates global protein translation whereas RNA-interference mediated HELZ suppression had the opposite effect. Although HELZ interacted with the poly(A)-binding protein (PABP) via its PAM2 motif, PABP was dispensable for HELZ function in protein translation. Importantly, downregulation of HELZ reduced translational initiation, resulting in the disassembly of polysomes, in a reduction of cell proliferation and hypophosphorylation of ribosomal protein S6.
authors.affiliation: Institute of Physiology and Zürich Center for Integrative Human Physiology ZIHP, University of Zürich UZH, Zürich, Switzerland.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Hasgall
authors.forename: David
authors.initials: D
authors.lastname: Hoogewijs
authors.forename: Marius B
authors.initials: MB
authors.lastname: Faza
authors.forename: Vikram G
authors.initials: VG
authors.lastname: Panse
authors.forename: Roland H
authors.initials: RH
authors.lastname: Wenger
authors.forename: Gieri
authors.initials: G
authors.lastname: Camenisch
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017124:Conserved Sequence; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010100:Oxygen / Q000494:pharmacology; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D020365:RNA Helicases / Q000737:chemistry / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000378:metabolism*; D020539:Sequence Analysis, Protein
chemical_list: D039102:Poly(A)-Binding Proteins; D038601:Ribosomal Protein S6; D008156:Luciferases; C562220:HELZ protein, mouse; C562219:MAPK4 protein, human; D020365:RNA Helicases; D010100:Oxygen