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Vol. 19, Issue 12, 5072-5081, December 2008

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Aftiphilin and -Synergin Are Required for Secretagogue Sensitivity of Weibel-Palade Bodies in Endothelial Cells

MRC Laboratory of Molecular Cell Biology, Cell Biology Unit and Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom

Submitted March 20, 2008; Revised September 2, 2008; Accepted September 16, 2008
Monitoring Editor: Francis A. Barr

Formation of secretory organelles requires the coupling of cargo selection to targeting into the correct exocytic pathway. Although the assembly of regulated secretory granules is driven in part by selective aggregation and retention of content, we recently reported that adaptor protein-1 (AP-1) recruitment of clathrin is essential to the initial formation of Weibel-Palade bodies (WPBs) at the trans-Golgi network. A selective co-aggregation process might include recruitment of components required for targeting to the regulated secretory pathway. However, we find that acquisition of the regulated secretory phenotype by WPBs in endothelial cells is coupled to but can be separated from formation of the distinctive granule core by ablation of the AP-1 effectors aftiphilin and -synergin. Their depletion by small interfering RNA leads to WPBs that fail to respond to secretagogue and release their content in an unregulated manner. We find that these non-responsive WPBs have density, markers of maturation, and highly multimerized von Willebrand factor similar to those of wild-type granules. Thus, by also recruiting aftiphilin/-synergin in addition to clathrin, AP-1 coordinates formation of WPBs with their acquisition of a regulated secretory phenotype.

Present address: * Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, University of Cambridge, Hills Rd., Cambridge CB2 0XY, United Kingdom.

Address correspondence to: Daniel F. Cutler (d.cutler{at}ucl.ac.uk)

Abbreviations used: GGA, Golgi-localized, -ear-containing; ADP, ribosylation factor (ARF)-binding proteins; HEK, human embryonic kidney; HMW, high molecular weight; HUVEC, human umbilical vein endothelial cell; LMW, low molecular weight; PMA, phorbol 12-myristate 13-acetate; ssHRP, signal sequence HRP; VWF, von Willebrand factor; WPB, Weibel-Palade body.