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J. Biol. Chem., Vol. 275, Issue 33, 25207-25215, August 18, 2000
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From the Vollum Institute for Advanced Biomedical Research, Oregon
Health Sciences University, Portland, Oregon 97201
Connexins, the integral membrane protein
constituents of gap junctions, are degraded at a rate
(t1/2 = 1.5-5 h) much faster than most other cell
surface proteins. Although the turnover of connexins has been shown to
be sensitive to inhibitors of either the lysosome or of the proteasome,
how connexins are targeted for degradation and whether this process can
be regulated to affect intercellular communication is unknown. We show
here that reducing connexin degradation with inhibitors of the
proteasome (but not with lysosomal blockers) is associated with a
striking increase in gap junction assembly and intercellular dye
transfer in cells inefficient in both processes under basal conditions.
The effect of proteasome inhibitors on wild-type connexin stability,
assembly, and function was mimicked by treatment of assembly-inefficient cells with inhibitors of protein synthesis such as
cycloheximide. Sensitivity of connexin degradation to cycloheximide,
but not to proteasome inhibitors, was abolished when connexins were
rendered structurally abnormal by perturbation of essential disulfide
bonds or by mutation. Our findings provide the first evidence that
intercellular communication can be up-regulated at the level of
connexin turnover and that a short-lived protein may be required for
conformationally mature connexins to become substrates of proteasomal degradation.
Regulation of Connexin Degradation as a Mechanism to Increase Gap
Junction Assembly and Function*
,
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Vollum Institute for
Advanced Biomedical Research L474, Oregon Health Sciences University,
3181 Southwest Sam Jackson Park Rd., Portland, OR 97201. Tel.:
503-494-1300; Fax: 503-494-8230; E-mail: Musill@ohsu.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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