title: Cotransin induces accumulation of a cytotoxic clusterin variant that cotranslationally rerouted to the cytosol.
abstract: Although clusterin (CLU) was originally identified as a secreted glycoprotein that plays cytoprotective role, several intracellular CLU variants have been recently identified in the diverse pathological conditions. The mechanistic basis of these variants is now believed to be alternative splicing and retrotranslocation. Here, we uncovered, an unglycosylated and signal sequence-unprocessed, CLU variant in the cytosol. This variant proved to be a product that cotranslationally rerouted to the cytosol during translocation. Cytosolic CLU was prone to aggregation at peri-nuclear region of cells and induced cell death. Signal sequence is shown to be an important determinant for cytosolic CLU generation and aggregation. These results provide not only a new mechanistic insight into the cytosolic CLU generation but also an idea for therapeutic mislocalization of CLU as a strategy for cancer treatment.
authors: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Ilho
authors: I
authors: Choi
authors: Jiyeon
authors: J
authors: Kim
authors: Joong-Yeol
authors: JY
authors: Park
authors: Sang-Wook
authors: SW
authors: Kang
mesh_terms: D000595:Amino Acid Sequence; D051152:Clusterin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011388:Prolactin / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D021382:Protein Sorting Signals / Q000235:genetics / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects
chemical_list: C495242:CLU protein, human; D051152:Clusterin; D050505:Mutant Proteins; D010456:Peptides, Cyclic; D021382:Protein Sorting Signals; C502316:cotransin; D011388:Prolactin