Selective inhibition of cotranslational translocation of vascular cell adhesion molecule 1

Jürgen Besemer, Hanna Harant, Shirley Wang, Berndt Oberhauser, Katharina Marquardt, Carolyn A. Foster, Erwin P. Schreiner, Jan E. de Vries (), Christiane Dascher-Nadel and Ivan J. D. Lindley
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Jürgen Besemer: Novartis Institutes for BioMedical Research
Hanna Harant: Novartis Institutes for BioMedical Research
Shirley Wang: Novartis Institutes for BioMedical Research
Berndt Oberhauser: Novartis Institutes for BioMedical Research
Katharina Marquardt: Novartis Institutes for BioMedical Research
Carolyn A. Foster: Novartis Institutes for BioMedical Research
Erwin P. Schreiner: Novartis Institutes for BioMedical Research
Jan E. de Vries: Novartis Institutes for BioMedical Research
Christiane Dascher-Nadel: Novartis Institutes for BioMedical Research
Ivan J. D. Lindley: Novartis Institutes for BioMedical Research

Nature, 2005, vol. 436, issue 7048, 290-293

Abstract: Abstract 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 intervention1,2,3. 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 Sec61β. 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.

Date: 2005
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DOI: 10.1038/nature03670

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