ER-degradation: reverse protein flow of no return

Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany.
The FASEB Journal (Impact Factor: 5.04). 01/1998; 11(14):1227-33.
Source: PubMed


The endoplasmic reticulum (ER) is the site of entry of proteins into the secretory pathway. It is responsible for proper folding of the proteins before delivery to their site of action. Furthermore, proofreading to detect malfolded or unnecessary proteins that have to be eliminated and regulation of protein levels are crucial ER functions. The ubiquitin-proteasome system, located in the cytoplasm, has emerged as the major ER degradation machinery. A multitude of ER resident as well as membrane-bound and soluble proteolytic substrates of the secretory pathway are retained in the ER and destined for degradation via this pathway. Their actual proteolysis is preceded by a retrograde transport to the cytoplasm. A key component of the translocation apparatus, Sec61p, is also the central subunit of the retrograde transport system. Other components of the translocon such as Sec63p or the lumenal chaperone BiP may also be involved in export to the cytosol. Novel ER membrane proteins such as Der1p, Der3p/Hrd1p, or Hrd3p might reprogram the translocon for retrograde transport. As ubiquitination is a prerequisite for degradation by the proteasome, exported proteins are ubiquitinated. Representatives of ER membrane-bound ubiquitin-conjugating enzymes, Ubc6p and Cue1p/Ubc7p, have been identified in yeast. Retrograde transport and ubiquitination seem to be coupled processes.

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Available from: Dieter Heinrich Wolf, Jan 13, 2014
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    • "In a concerted manner, Glucosidases I and II along with lectin chaperones calnexin and calreticulin participate to the ER-retention of nascent glycoproteins until they are properly folded and thus preventing their aggregation [19]. Polypeptides that succeed in reaching their mature conformation are released from the lectin-proteins as soon as their folding process is completed [20], [21], and the unfolded and or misfolded glycoproteins are delivered to cytosolic degradation mediated by the ubiquitin-proteasome pathway, a process known as an ER-associated degradation (ERAD) [22], [23], [24]. Moreover, accumulation of unfolded proteins in the ER induces a condition known as ER stress that in turn, triggers the increased expression of BiP and other chaperones, a phenomenon termed “unfolded protein response” (UPR) [25]. "
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    • "For this purpose misfolded proteins have to be retrotranslocated out of the ER, polyubiquitylated and delivered to the proteasome. This process is called ER-associated degradation (ERAD) [12] [13] [14] [15] [16] [17]. Prior to retrotranslocation a quality control (QC) system of the ER has to differentiate between terminally misfolded proteins and folding intermediates. "
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    • "j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / b b a m c r Doa10 (Fig. 1) [12] [13] [14] [15] [16]. Overload of misfolded proteins leads to the induction of the unfolded protein response (UPR), a mechanism, which upregulates proteins necessary for dealing with this unfavorable situation. "
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