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Vol. 20, Issue 10, 2593-2604, May 15, 2009

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ERp29 Restricts Connexin43 Oligomerization in the Endoplasmic Reticulum

Shamie Das^*,, Tekla D. Smith^*,, Jayasri Das Sarma, Jeffrey D. Ritzenthaler^*, Jose Maza^*, Benjamin E. Kaplan^*, Leslie A. Cunningham^*, Laurence Suaud, Michael J. Hubbard^||, Ronald C. Rubenstein, and Michael Koval^*,¶

*Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and ^¶Department of Cell Biology, Emory University School of Medicine, Atlanta GA 30322; Neuroscience Group, Indian Institute of Science Education and Research, Kolkata, India 700106; Division of Pulmonary Medicine, Children's Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and ^||Department of Paediatrics, University of Melbourne, Melbourne, Victoria 3052, Australia

Submitted August 1, 2008; Revised March 12, 2009; Accepted March 13, 2009
Monitoring Editor: Jeffrey L. Brodsky

Connexin43 (Cx43) is a gap junction protein that forms multimeric channels that enable intercellular communication through the direct transfer of signals and metabolites. Although most multimeric protein complexes form in the endoplasmic reticulum (ER), Cx43 seems to exit from the ER as monomers and subsequently oligomerizes in the Golgi complex. This suggests that one or more protein chaperones inhibit premature Cx43 oligomerization in the ER. Here, we provide evidence that an ER-localized, 29-kDa thioredoxin-family protein (ERp29) regulates Cx43 trafficking and function. Interfering with ERp29 function destabilized monomeric Cx43 oligomerization in the ER, caused increased Cx43 accumulation in the Golgi apparatus, reduced transport of Cx43 to the plasma membrane, and inhibited gap junctional communication. ERp29 also formed a specific complex with monomeric Cx43. Together, this supports a new role for ERp29 as a chaperone that helps stabilize monomeric Cx43 to enable oligomerization to occur in the Golgi apparatus.

These authors contributed equally to this work.

Address correspondence to: Michael Koval (mhkoval{at}emory.edu)