title: Geldanamycin Enhances Retrograde Transport of Shiga Toxin in HEp-2 Cells.
abstract: The heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA) has been shown to alter endosomal sorting, diverting cargo destined for the recycling pathway into the lysosomal pathway. Here we investigated whether GA also affects the sorting of cargo into the retrograde pathway from endosomes to the Golgi apparatus. As a model cargo we used the bacterial toxin Shiga toxin, which exploits the retrograde pathway as an entry route to the cytosol. Indeed, GA treatment of HEp-2 cells strongly increased the Shiga toxin transport to the Golgi apparatus. The enhanced Golgi transport was not due to increased endocytic uptake of the toxin or perturbed recycling, suggesting that GA selectively enhances endosomal sorting into the retrograde pathway. Moreover, GA activated p38 and both inhibitors of p38 or its substrate MK2 partially counteracted the GA-induced increase in Shiga toxin transport. Thus, our data suggest that GA-induced p38 and MK2 activation participate in the increased Shiga toxin transport to the Golgi apparatus.
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
authors.forename: Anne Berit
authors.initials: AB
authors.lastname: Dyve Lingelem
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway; Department of Biosciences, University of Oslo, Oslo, Norway.
authors.forename: Ieva Ailte
authors.initials: IA
authors.lastname: Hjelseth
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
authors.forename: Roger
authors.initials: R
authors.lastname: Simm
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
authors.forename: Maria Lyngaas
authors.initials: ML
authors.lastname: Torgersen
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway; Department of Biosciences, University of Oslo, Oslo, Norway.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Sandvig
mesh_terms: D001427:Bacterial Toxins / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects*; D045744:Cell Line, Tumor; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects*; D022621:Shiga Toxin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D001427:Bacterial Toxins; D016227:Benzoquinones; D047908:Intracellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic; D017346:Protein Serine-Threonine Kinases; D022621:Shiga Toxin; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C001277:geldanamycin