title: Role of phospholipase A(2) in retrograde transport of ricin.
abstract: Ricin is a protein toxin classified as a bioterror agent, for which there are no known treatment options available after intoxication. It is composed of an enzymatically active A-chain connected by a disulfide bond to a cell binding B-chain. After internalization by endocytosis, ricin is transported retrogradely to the Golgi and ER, from where the ricin A-chain is translocated to the cytosol where it inhibits protein synthesis and thus induces cell death. We have identified cytoplasmic phospholipase A(2) (PLA(2)) as an important factor in ricin retrograde transport. Inhibition of PLA(2) protects against ricin challenge, however the toxin can still be endocytosed and transported to the Golgi. Interestingly, ricin transport from the Golgi to the ER is strongly impaired in response to PLA(2) inhibition. Confocal microscopy analysis shows that ricin is still colocalized with the trans-Golgi marker TGN46 in the presence of PLA(2) inhibitor, but less is colocalized with the cis-Golgi marker GM130. We propose that PLA(2) inhibition results in impaired ricin transport through the Golgi stack, thus preventing it from reaching the ER. Consequently, ricin cannot be translocated to the cytosol to exert its toxic action.
authors: Centre for Cancer Biomedicine, Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0310 Oslo, Norway. tove.irene.klokk@rr-research.no
authors: Tove Irene
authors: TI
authors: Klokk
authors: Anne Berit Dyve
authors: AB
authors: Lingelem
authors: Anne-Grethe
authors: AG
authors: Myrann
authors: Kirsten
authors: K
authors: Sandvig
mesh_terms: D045744:Cell Line, Tumor; D002619:Chemical Warfare Agents / Q000378:metabolism*; D002723:Chlorobenzoates / Q000494:pharmacology; D002934:Cinnamates / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D011753:Pyrones / Q000494:pharmacology; D012276:Ricin / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000494:pharmacology; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D002619:Chemical Warfare Agents; D002723:Chlorobenzoates; D002934:Cinnamates; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D064801:Phospholipase A2 Inhibitors; D011753:Pyrones; D062367:ortho-Aminobenzoates; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D012276:Ricin; C060048:2-(4-amylcinnamoyl)amino-4-chlorobenzoic acid; D054467:Phospholipases A2