FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2999641369> ?p ?o ?g. }

• W2999641369 abstract "Abstract Factor VIII (FVIII) is the coagulation factor deficient in hemophilia A, which is treated by protein replacement. Unfortunately, this regimen is costly due to the expense of producing recombinant FVIII as a consequence of its low level secretion. FVIII expression activates the endoplasmic reticulum (ER) stress response, causes oxidative stress and induces apoptosis. Importantly, little is known about the factors that cause protein misfolding and aggregation in metazoans. Here we identified intrinsic and extrinsic factors that cause FVIII to form aggregates in the ER. We show that FVIII forms amyloid-like fibrils within the ER upon increased FVIII synthesis or inhibition of glucose metabolism. Significantly, FVIII amyloids can be dissolved upon restoration of glucose metabolism to produce functional secreted FVIII. Two ER chaperones and their co-chaperones, BiP and CANX/CRT, promote FVIII solubility in the ER, where the former is also required for disaggregation. A short aggregation motif in the FVIII A1 domain (termed Aggron) is necessary and sufficient to seed β-sheet polymerization and BiP binding to this Aggron prevents amyloidogenesis. Our findings provide novel insight into mechanisms that limit FVIII secretion and ER protein folding in general and have implication for ongoing hemophilia A gene therapy clinical trials. Key Points - FVIII forms amyloid aggregates in the ER that are dissolved in a chaperone- and glucose-dependent manner to produce secreted active FVIII. - A short amino acid sequence in the A1 domain causes β sheet polymerization and ER chaperone BiP binding to this site prevents aggregation." @default.
• W2999641369 created "2020-01-23" @default.
• W2999641369 creator A5001236608 @default.
• W2999641369 creator A5001369487 @default.
• W2999641369 creator A5012514266 @default.
• W2999641369 creator A5014651890 @default.
• W2999641369 creator A5015378855 @default.
• W2999641369 creator A5033062448 @default.
• W2999641369 creator A5038494526 @default.
• W2999641369 creator A5055597053 @default.
• W2999641369 creator A5056689193 @default.
• W2999641369 creator A5057457409 @default.
• W2999641369 creator A5064229418 @default.
• W2999641369 creator A5070880079 @default.
• W2999641369 creator A5089509887 @default.
• W2999641369 date "2020-01-14" @default.
• W2999641369 modified "2023-10-17" @default.
• W2999641369 title "Factor VIII exhibits chaperone-dependent and glucose-regulated reversible amyloid formation in the endoplasmic reticulum" @default.
• W2999641369 cites W1514223875 @default.
• W2999641369 cites W1540151595 @default.
• W2999641369 cites W1602776657 @default.
• W2999641369 cites W174468170 @default.
• W2999641369 cites W1967104104 @default.
• W2999641369 cites W1977026532 @default.
• W2999641369 cites W1977603207 @default.
• W2999641369 cites W2002741069 @default.
• W2999641369 cites W2009604591 @default.
• W2999641369 cites W2012896303 @default.
• W2999641369 cites W2021283345 @default.
• W2999641369 cites W2021739193 @default.
• W2999641369 cites W2027839322 @default.
• W2999641369 cites W2028634229 @default.
• W2999641369 cites W2036160555 @default.
• W2999641369 cites W2038527888 @default.
• W2999641369 cites W2053823780 @default.
• W2999641369 cites W2058468253 @default.
• W2999641369 cites W2065278356 @default.
• W2999641369 cites W2065931823 @default.
• W2999641369 cites W2066226950 @default.
• W2999641369 cites W2075182910 @default.
• W2999641369 cites W2075623608 @default.
• W2999641369 cites W2079473693 @default.
• W2999641369 cites W2085390667 @default.
• W2999641369 cites W2091629675 @default.
• W2999641369 cites W2095498248 @default.
• W2999641369 cites W2105693459 @default.
• W2999641369 cites W2106868839 @default.
• W2999641369 cites W2115537581 @default.
• W2999641369 cites W2129058679 @default.
• W2999641369 cites W2129751025 @default.
• W2999641369 cites W2150202137 @default.
• W2999641369 cites W2158636606 @default.
• W2999641369 cites W2263498456 @default.
• W2999641369 cites W2269867552 @default.
• W2999641369 cites W2273902252 @default.
• W2999641369 cites W2518363707 @default.
• W2999641369 cites W2751898404 @default.
• W2999641369 cites W2765807058 @default.
• W2999641369 cites W2898124960 @default.
• W2999641369 cites W2951513309 @default.
• W2999641369 cites W62793449 @default.
• W2999641369 doi "https://doi.org/10.1101/2020.01.13.905190" @default.
• W2999641369 hasPublicationYear "2020" @default.
• W2999641369 type Work @default.
• W2999641369 sameAs 2999641369 @default.
• W2999641369 citedByCount "0" @default.
• W2999641369 crossrefType "posted-content" @default.
• W2999641369 hasAuthorship W2999641369A5001236608 @default.
• W2999641369 hasAuthorship W2999641369A5001369487 @default.
• W2999641369 hasAuthorship W2999641369A5012514266 @default.
• W2999641369 hasAuthorship W2999641369A5014651890 @default.
• W2999641369 hasAuthorship W2999641369A5015378855 @default.
• W2999641369 hasAuthorship W2999641369A5033062448 @default.
• W2999641369 hasAuthorship W2999641369A5038494526 @default.
• W2999641369 hasAuthorship W2999641369A5055597053 @default.
• W2999641369 hasAuthorship W2999641369A5056689193 @default.
• W2999641369 hasAuthorship W2999641369A5057457409 @default.
• W2999641369 hasAuthorship W2999641369A5064229418 @default.
• W2999641369 hasAuthorship W2999641369A5070880079 @default.
• W2999641369 hasAuthorship W2999641369A5089509887 @default.
• W2999641369 hasBestOaLocation W29996413691 @default.
• W2999641369 hasConcept C136238340 @default.
• W2999641369 hasConcept C139447449 @default.
• W2999641369 hasConcept C142724271 @default.
• W2999641369 hasConcept C158617107 @default.
• W2999641369 hasConcept C179104552 @default.
• W2999641369 hasConcept C185592680 @default.
• W2999641369 hasConcept C204328495 @default.
• W2999641369 hasConcept C2775962898 @default.
• W2999641369 hasConcept C2777633098 @default.
• W2999641369 hasConcept C49039625 @default.
• W2999641369 hasConcept C55493867 @default.
• W2999641369 hasConcept C61397870 @default.
• W2999641369 hasConcept C71924100 @default.
• W2999641369 hasConcept C86803240 @default.
• W2999641369 hasConcept C95444343 @default.
• W2999641369 hasConceptScore W2999641369C136238340 @default.
• W2999641369 hasConceptScore W2999641369C139447449 @default.
• W2999641369 hasConceptScore W2999641369C142724271 @default.
• W2999641369 hasConceptScore W2999641369C158617107 @default.

• next