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MBC in Press, published online ahead of print January 20, 2010
Mol. Biol. Cell 10.1091/mbc.E09-10-0914

A more recent version of this article appeared on March 15, 2010
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Submitted on November 2, 2009
Revised on December 17, 2009
Accepted on January 13, 2010

Vesicular Calcium Regulates Coat Retention, Fusogenicity, and Size of Pre-Golgi Intermediates

Marvin Bentley,*{dagger} Deborah C. Nycz,*{dagger} Ashwini Joglekar,*{ddagger} Ismene Fertschai,{sect} Roland Malli,{sect} Wolfgang F. Graier,{sect} and Jesse C. Hay*

*Division of Biological Sciences and Center for Structural and Functional Neuroscience, The University of Montana, Missoula Montana 59812-4824; {sect}Center of Molecular Medicine, Medical University of Graz, 8010 Graz, Austria

Monitoring Editor: Adam Linstedt

The significance and extent of Ca2+ regulation of the biosynthetic secretory pathway has been difficult to establish, and our knowledge of regulatory relationships integrating Ca2+ with vesicle coats and function is rudimentary. Here we investigated potential roles and mechanisms of luminal Ca2+ in the early secretory pathway. Specific depletion of luminal Ca2+ in living NRK cells using cyclopiazonic acid (CPA) resulted in the extreme expansion of vesicular tubular cluster (VTC) elements. Consistent with this, a suppressive role for vesicle-associated Ca2+ in COPII vesicle homotypic fusion was demonstrated in vitro using Ca2+ chelators. The EF-hand-containing protein apoptosis-linked gene 2 (ALG-2), previously implicated in the stabilization of sec31 at ER exit sites, inhibited COPII vesicle fusion in a Ca2+-requiring manner, suggesting that ALG-2 may be a sensor for the effects of vesicular Ca2+ on homotypic fusion. Immunoisolation established that Ca2+ chelation inhibits and ALG-2 specifically favors residual retention of the COPII outer shell protein sec31 on pre-Golgi fusion intermediates. We conclude that vesicle-associated Ca2+, acting though ALG-2, favors the retention of residual coat molecules which appear to suppress membrane fusion. We propose that in cells, these Ca2+-dependent mechanisms temporally regulate COPII vesicle interactions, VTC biogenesis, cargo sorting, and VTC maturation.

{dagger}These authors contributed equally to this work.

{ddagger}Present address: Evolvus, Inc., Pune, India.

Address correspondence to: Jesse C. Hay (jesse.hay{at}umontana.edu)






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