PubMed · 12073349
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Yuval Shimoni, Randy Schekman. 2002. Vesicle budding from endoplasmic reticulum.. https://doi.org/10.1016/s0076-6879(02)51852-8
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Secretory proteins are transported from the endoplasmic reticulum (ER) to the Golgi complex in vesicles coated with coat protein complex II (COPII). The incorporation of certain transport molecules (cargo) into the COPII vesicles is thought to be mediated by cargo receptors. Here we show that Emp47p, a type-I membrane protein, is specifically required for the transport of an integral membrane protein, Emp46p, from the ER. Exit of Emp46p from the ER was saturable and dependent on the expression level of Emp47p. Emp46p binding to Emp47p occurs in the ER through the coiled-coil region in the luminal domains of both Emp47p and Emp46p, and dissociation occurs in the Golgi. Further, this coiled-coil region is also required for Emp47p to form an oligomeric complex of itself in the ER, which is essential for exit of Emp47p from the ER. Our results suggest that Emp47p is a receptor protein for Emp46p that allows for the selective transport of this protein, and this event involves receptor oligomerization.
Newly synthesized proteins that do not fold correctly in the ER are targeted for ER-associated protein degradation (ERAD) through distinct sorting mechanisms; soluble ERAD substrates require ER-Golgi transport and retrieval for degradation, whereas transmembrane ERAD substrates are retained in the ER. Retained transmembrane proteins are often sequestered into specialized ER subdomains, but the relevance of such sequestration to proteasomal degradation has not been explored. We used the yeast Saccharomyces cerevisiae and a model ERAD substrate, the cystic fibrosis transmembrane conductance regulator (CFTR), to explore whether CFTR is sequestered before degradation, to identify the molecular machinery regulating sequestration, and to analyze the relationship between sequestration and degradation. We report that CFTR is sequestered into ER subdomains containing the chaperone Kar2p, and that sequestration and CFTR degradation are disrupted in sec12ts strain (mutant in guanine-nucleotide exchange factor for Sar1p), sec13ts strain (mutant in the Sec13p component of COPII), and sec23ts strain (mutant in the Sec23p component of COPII) grown at restrictive temperature. The function of the Sar1p/COPII machinery in CFTR sequestration and degradation is independent of its role in ER-Golgi traffic. We propose that Sar1p/COPII-mediated sorting of CFTR into ER subdomains is essential for its entry into the proteasomal degradation pathway. These findings reveal a new aspect of the degradative mechanism, and suggest functional crosstalk between the secretory and the degradative pathways.
Ubiquitination is important for a broad array of cellular functions. Although reversal of this process, de-ubiquitination, most probably represents an important regulatory step contributing to cellular homeostasis, the specificity and properties of de-ubiquitination enzymes remain poorly understood. Here, we show that the Saccharomyces cerevisiae ubiquitin protease Ubp3 requires an additional protein, Bre5, to form an active de-ubiquitination complex that cleaves ubiquitin from specific substrates. In particular, this complex rescues Sec23p, a COPII subunit essential for the transport between the endoplasmic reticulum and the Golgi apparatus, from degradation by the proteasome. This probably contributes to maintaining and adapting a Sec23 expression level that is compatible with an efficient secretion pathway, and consequently with cell growth and viability.