Limiting transport steps and novel interactions of Connexin-43 along the secretory pathway |
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Authors: | Irina V Majoul Daria Onichtchouk Eugenia Butkevich Dirk Wenzel Levon M Chailakhyan Rainer Duden |
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Institution: | 1.Institute of Biology, Center for Structural and Cell Biology in Medicine,University of Lübeck,Lübeck,Germany;2.Developmental Biology Unit, Department of Biology I,University of Freiburg,Freiburg,Germany;3.Department of Neurophysiology,University of G?ttingen,G?ttingen,Germany;4.Department of Neurobiology, Max-Planck-Institute of Biophysical Chemistry,G?ttingen,Germany;5.Department of Cellular Biophysics and Intercellular Communications, Institute of Theoretical and Experimental Biophysics,Russian Academy of Sciences,Moscow,Russia |
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Abstract: | Connexins are four-transmembrane-domain proteins expressed in all vertebrates which form permeable gap junction channels that
connect cells. Here, we analysed Connexin-43 (Cx43) transport to the plasma membrane and studied the effects of small GTPases
acting along the secretory pathway. We show that both GTP- and GDP-restricted Sar1 prevents exit of Cx43 from the endoplasmic
reticulum (ER), but only GTP-restricted Sar1 arrests Cx43 in COP II-coated ER exit sites and accumulates 14-3-3 proteins in
the ER fraction. FRET-FLIM data confirm that already in ER exit sites Cx43 exists in oligomeric form, suggesting an in vivo
role for 14-3-3 in Cx43 oligomerization. Exit of Cx43 from the ER can be blocked by other factors—such as expression of the
β subunit of the COP I coat or p50/dynamitin that acts on the microtubule-based dynein motor complex. GTP-restricted Arf1
blocks Cx43 in the Golgi. Lastly, we show that GTP-restricted Arf6 removes Cx43 gap junction plaques from the cell–cell interface
and targets them to degradation. These data provide a molecular explanation of how small GTPases act to regulate Cx43 transport
through the secretory pathway, facilitating or abolishing cell–cell communication through gap junctions. |
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Keywords: | Connexins Gap junction Arf COP FRET |
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