Selective inhibition of cotranslational translocation of vascular cell adhesion molecule 1.
Increased expression of vascular cell adhesion molecule 1 (VCAM1) is associated with a variety of chronic inflammatory conditions, making its expression and function a target for therapeutic intervention. We have recently identified CAM741, a derivative of a fungus-derived cyclopeptolide that acts as a selective inhibitor of VCAM1 synthesis in endothelial cells. Here we show that the compound represses the biosynthesis of VCAM1 in cells by blocking the process of cotranslational translocation, which is dependent on the signal peptide of VCAM1. CAM741 does not inhibit targeting of the VCAM1 nascent chains to the translocon channel but prevents translocation to the luminal side of the endoplasmic reticulum (ER), through a process that involves the translocon component Sec61beta. Consequently, the VCAM1 precursor protein is synthesized towards the cytosolic compartment of the cells, where it is degraded. Our results indicate that the inhibition of cotranslational translocation with low-molecular-mass compounds, using specificity conferred by signal peptides, can modulate the biosynthesis of certain secreted and/or membrane proteins. In addition, they highlight cotranslational translocation at the ER membrane as a potential target for drug discovery.
Besemer
Jürgen
J
Novartis Institutes for BioMedical Research, Brunner Strasse 59, A-1235 Vienna, Austria.
Harant
Hanna
H
Wang
Shirley
S
Oberhauser
Berndt
B
Marquardt
Katharina
K
Foster
Carolyn A
CA
Schreiner
Erwin P
EP
de Vries
Jan E
JE
Dascher-Nadel
Christiane
C
Lindley
Ivan J D
IJ
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D011499:Protein Processing, Post-Translational; D021382:Protein Sorting Signals / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects; D000069816:SEC Translocation Channels; D012680:Sensitivity and Specificity; D017384:Sequence Deletion; D013379:Substrate Specificity; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*
C502318:CAM741; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D021382:Protein Sorting Signals; D000069816:SEC Translocation Channels; D019010:Vascular Cell Adhesion Molecule-1; D010447:Peptide Hydrolases