Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endoplasmic reticulum (ER) harbors a protein quality control system, which monitors protein folding in the ER. Elimination of malfolded proteins is an important function of this protein quality control. Earlier studies with various soluble and transmembrane ER-associated degradation (ERAD) substrates revealed differences in the ER degradation machinery used. To unravel the nature of these differences we generated two type I membrane ERAD substrates carrying malfolded carboxypeptidase yscY (CPY*) as the ER-luminal ERAD recognition motif. Whereas the first, CT* (CPY*-TM), has no cytoplasmic domain, the second, CTG*, has the green fluorescent protein present in the cytosol. Together with CPY*, these three substrates represent topologically diverse malfolded proteins, degraded via ERAD. Our data show that degradation of all three proteins is dependent on the ubiquitin-proteasome system involving the ubiquitin-protein ligase complex Der3/Hrd1p-Hrd3p, the ubiquitin conjugating enzymes Ubc1p and Ubc7p, as well as the AAA-ATPase complex Cdc48-Ufd1-Npl4 and the 26S proteasome. In contrast to soluble CPY*, degradation of the membrane proteins CT* and CTG* does not require the ER proteins Kar2p (BiP) and Der1p. Instead, CTG* degradation requires cytosolic Hsp70, Hsp40, and Hsp104p chaperones.
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PMID:Use of modular substrates demonstrates mechanistic diversity and reveals differences in chaperone requirement of ERAD. 1284 7

Cdc48, known as p97 or valosin-containing protein (VCP) in mammals, is an abundant AAA-ATPase that is essential for many ubiquitin-dependent processes. One well-documented role for Cdc48 is in facilitating the delivery of ubiquitylated misfolded endoplasmic reticulum proteins to the proteasome for degradation. By contrast, the role for Cdc48 in misfolded protein degradation in the nucleus is unknown. In the budding yeast Saccharomyces cerevisiae, degradation of misfolded proteins in the nucleus is primarily mediated by the nuclear-localized ubiquitin-protein ligase San1, which ubiquitylates misfolded nuclear proteins for proteasomal degradation. Here, we find that, although Cdc48 is involved in the degradation of some San1 substrates, it is not universally required. The difference in the requirement for Cdc48 correlates with the insolubility of the San1 substrate. The more insoluble the substrate, the more its degradation requires Cdc48. Expression of Cdc48-dependent San1 substrates in mutant cdc48 cells results in increased substrate insolubility, larger inclusion formation and reduced cell viability. Substrate ubiquitylation is increased in mutant cdc48 cells, suggesting that Cdc48 functions downstream of San1. Taken together, we propose that Cdc48 acts, in part, to maintain the solubility or reverse the aggregation of insoluble misfolded proteins prior to their proteasomal degradation.
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PMID:The requirement for Cdc48/p97 in nuclear protein quality control degradation depends on the substrate and correlates with substrate insolubility. 2456 78

Intracellular acting protein exotoxins produced by bacteria and plants are important molecular determinants that drive numerous human diseases. A subset of these toxins, the cytolethal distending toxins (CDTs), are encoded by several Gram-negative pathogens and have been proposed to enhance virulence by allowing evasion of the immune system. CDTs are trafficked in a retrograde manner from the cell surface through the Golgi apparatus and into the endoplasmic reticulum (ER) before ultimately reaching the host cell nucleus. However, the mechanism by which CDTs exit the ER is not known. Here we show that three central components of the host ER associated degradation (ERAD) machinery, Derlin-2 (Derl2), the E3 ubiquitin-protein ligase Hrd1, and the AAA ATPase p97, are required for intoxication by some CDTs. Complementation of Derl2-deficient cells with Derl2:Derl1 chimeras identified two previously uncharacterized functional domains in Derl2, the N-terminal 88 amino acids and the second ER-luminal loop, as required for intoxication by the CDT encoded by Haemophilus ducreyi (Hd-CDT). In contrast, two motifs required for Derlin-dependent retrotranslocation of ERAD substrates, a conserved WR motif and an SHP box that mediates interaction with the AAA ATPase p97, were found to be dispensable for Hd-CDT intoxication. Interestingly, this previously undescribed mechanism is shared with the plant toxin ricin. These data reveal a requirement for multiple components of the ERAD pathway for CDT intoxication and provide insight into a Derl2-dependent pathway exploited by retrograde trafficking toxins.
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PMID:Cytolethal distending toxins require components of the ER-associated degradation pathway for host cell entry. 2507 82

Protein quality mechanisms are fundamental for proteostasis of eukaryotic cells. Endoplasmic reticulum-associated degradation (ERAD) is a well-studied pathway that ensures quality control of secretory and endoplasmic reticulum (ER)-resident proteins. Different branches of ERAD are involved in degradation of malfolded secretory proteins, depending on the localization of the misfolded part, the ER lumen (ERAD-L), the ER membrane (ERAD-M), and the cytosol (ERAD-C). Here we report that modification of several ER transmembrane proteins with the photosensitive degron (psd) module resulted in light-dependent degradation of the membrane proteins via the ERAD-C pathway. We found dependency on the ubiquitylation machinery including the ubiquitin-activating enzyme Uba1, the ubiquitin--conjugating enzymes Ubc6 and Ubc7, and the ubiquitin-protein ligase Doa10. Moreover, we found involvement of the Cdc48 AAA-ATPase complex members Ufd1 and Npl4, as well as the proteasome, in degradation of Sec62-myc-psd. Thus, our work shows that ERAD-C substrates can be systematically generated via synthetic degron constructs, which facilitates future investigations of the ERAD-C pathway.
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PMID:Degradation of integral membrane proteins modified with the photosensitive degron module requires the cytosolic endoplasmic reticulum-associated degradation pathway. 3141 39