title: The lysophospholipid acyltransferase antagonist CI-976 inhibits a late step in COPII vesicle budding.
abstract: The mechanism of coat protein (COP)II vesicle fission from the endoplasmic reticulum (ER) remains unclear. Lysophospholipid acyltransferases (LPATs) catalyze the conversion of various lysophospholipids to phospholipids, a process that can promote spontaneous changes in membrane curvature. Here, we show that 2,2-methyl-N-(2,4,6,-trimethoxyphenyl)dodecanamide (CI-976), a potent LPAT inhibitor, reversibly inhibited export from the ER in vivo and the formation of COPII vesicles in vitro. Moreover, CI-976 caused the rapid and reversible accumulation of cargo at ER exit sites (ERESs) containing the COPII coat components Sec23/24 and Sec13/31 and a marked enhancement of Sar1p-mediated tubule formation from ERESs, suggesting that CI-976 inhibits the fission of assembled COPII budding elements. These results identify a small molecule inhibitor of a very late step in COPII vesicle formation, consistent with fission inhibition, and demonstrate that this step is likely facilitated by an ER-associated LPAT.
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA. wjb5@cornell.edu
authors.forename: William J
authors.initials: WJ
authors.lastname: Brown
authors.forename: Helen
authors.initials: H
authors.lastname: Plutner
authors.forename: Daniel
authors.initials: D
authors.lastname: Drecktrah
authors.forename: Bret L
authors.initials: BL
authors.lastname: Judson
authors.forename: William E
authors.initials: WE
authors.lastname: Balch
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000813:Anilides / Q000378:metabolism*; D000818:Animals; D022181:COP-Coated Vesicles / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000378:metabolism
chemical_list: D000813:Anilides; D004791:Enzyme Inhibitors; C028391:G protein, vesicular stomatitis virus; D008562:Membrane Glycoproteins; D033921:Vesicular Transport Proteins; D014759:Viral Envelope Proteins; C069304:PD 128042; D006160:Guanosine Triphosphate; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C487879:SAR1 protein, rat; D020559:Monomeric GTP-Binding Proteins