title: Manganese induces oligomerization to promote down-regulation of the intracellular trafficking receptor used by Shiga toxin.
abstract: Manganese (Mn) protects cells against lethal doses of purified Shiga toxin by causing the degradation of the cycling transmembrane protein GPP130, which the toxin uses as a trafficking receptor. Mn-induced GPP130 down-regulation, in addition to being a potential therapeutic approach against Shiga toxicosis, is a model for the study of metal-regulated protein sorting. Significantly, however, the mechanism by which Mn regulates GPP130 trafficking is unknown. Here we show that a transferable trafficking determinant within GPP130 bound Mn and that Mn binding induced GPP130 oligomerization in the Golgi. Alanine substitutions blocking Mn binding abrogated both oligomerization of GPP130 and GPP130 sorting from the Golgi to lysosomes. Further, oligomerization was sufficient because forced aggregation, using a drug-controlled polymerization domain, redirected GPP130 to lysosomes in the absence of Mn. These experiments reveal metal-induced oligomerization as a Golgi sorting mechanism for a medically relevant receptor for Shiga toxin.
authors: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213.
authors: Ritika
authors: R
authors: Tewari
authors: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213.
authors: Timothy
authors: T
authors: Jarvela
authors: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213 linstedt@andrew.cmu.edu.
authors: Adam D
authors: AD
authors: Linstedt
mesh_terms: D000409:Alanine / Q000737:chemistry; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004405:Dysentery, Bacillary / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008345:Manganese / Q000737:chemistry / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects*; D021381:Protein Transport; D022621:Shiga Toxin / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: C107340:GOLIM4 protein, human; D033921:Vesicular Transport Proteins; D008345:Manganese; D022621:Shiga Toxin; D000409:Alanine