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Published 29 April 2002. doi:10.1083/jcb.200111045
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© The Rockefeller University Press, 0021-9525/2002/4/381 $5.00
The Journal of Cell Biology, Volume 157, Number 3, April 29, 2002 381-394

Article

 Dislocation and degradation from the ER are regulated by cytosolic stress

Judy K. VanSlyke and Linda S. Musil

Division of Molecular Medicine, Oregon Health Sciences University, Portland, OR 97201

Address correspondence to Linda S. Musil, Division of Molecular Medicine NRC3, Oregon Health Sciences University, 3181 Southwest Sam Jackson Park Rd., Portland, OR 97201. Tel.: (503) 494-1300. Fax: (503) 494-7368. E-mail: Musill{at}OHSU.edu

Akey step in ER-associated degradation (ERAD) is dislocation of the substrate protein from the ER into the cytosol to gain access to the proteasome. Very little is known about how this process is regulated, especially in the case of polytopic proteins. Using pulse-chase analysis combined with subcellular fractionation, we show that connexins, the four transmembrane structural components of gap junctions, can be chased in an intact form from the ER membrane into the cytosol of proteasome inhibitor–treated cells. Dislocation of endogenously expressed connexin from the ER was reduced 50–80% when the cytosolic heat shock response was induced by mild oxidative or thermal stress, but not by treatments that instead upregulate the ER unfolded protein response. Cytosolic but not ER stresses slowed the normally rapid degradation of connexins, and led to a striking increase in gap junction formation and function in otherwise assembly-inefficient cell types. These treatments also inhibited the dislocation and turnover of a connexin-unrelated ERAD substrate, unassembled major histocompatibility complex class I heavy chain. Our findings demonstrate that dislocation is negatively regulated by physiologically relevant, nonlethal stress. They also reveal a previously unrecognized relationship between cytosolic stress and intercellular communication.

Key Words: endoplasmic reticulum; proteasome; heat-shock response; connexins; gap junctions


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