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Titel: Boosting endoplasmic reticulum folding capacity reduces unfolded protein response activation and intracellular accumulation of human kidney anion exchanger 1 in Saccharomyces cerevisiae
VerfasserIn: Li, Xiaobing
Cordat, Emmanuelle
Schmitt, Manfred J.
Becker, Björn
Sprache: Englisch
Titel: Yeast
Bandnummer: 38
Heft: 9
Seiten: 521-534
Verlag/Plattform: Wiley
Erscheinungsjahr: 2021
Freie Schlagwörter: chaperone
ER stress
kidney anion exchanger 1 (kAE1)
plasma membrane
unfolded protein response (UPR
yeast model organism
DDC-Sachgruppe: 610 Medizin, Gesundheit
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: Human kidney anion exchanger 1 (kAE1) facilitates simultaneous efflux of bicarbonate and absorption of chloride at the basolateral membrane of α-intercalated cells. In these cells, kAE1 contributes to systemic acid–base balance along with the proton pump v-H+-ATPase and the cytosolic carbonic anhydrase II. Recent electron microscopy analyses in yeast demonstrate that heterologous expression of several kAE1 variants causes a massive accumulation of the anion transporter in intracellular membrane structures. Here, we examined the origin of these kAE1 aggregations in more detail. Using various biochemical techniques and advanced light and electron microscopy, we showed that accumulation of kAE1 mainly occurs in endoplasmic reticulum (ER) membranes which eventually leads to strong unfolded protein response (UPR) activation and severe growth defect in kAE1 expressing yeast cells. Furthermore, our data indicate that UPR activation is dose dependent and uncoupled from the bicarbonate transport activity. By using truncated kAE1 variants, we identified the C-terminal region of kAE1 as crucial factor for the increased ER stress level. Finally, a redistribution of ER-localized kAE1 to the cell periphery was achieved by boosting the ER folding capacity. Our findings not only demonstrate a promising strategy for preventing intracellular kAE1 accumulation and improving kAE1 plasma membrane targeting but also highlight the versatility of yeast as model to investigate kAE1-related research questions including the analysis of structural features, protein degradation and trafficking. Furthermore, our approach might be a promising strategy for future analyses to further optimize the cell surface targeting of other disease-related PM proteins, not only in yeast but also in mammalian cells. Take Away We analysed the intracellular transport of human kAE1 to the yeast plasma membrane. We studied the effect of human kAE1 expression on yeast growth and UPR activation. We investigated the impact of different kAE1 truncation variants on UPR induction We implemented intervention strategies to improve PM targeting of kAE1.
DOI der Erstveröffentlichung: 10.1002/yea.3652
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-346622
hdl:20.500.11880/31729
http://dx.doi.org/10.22028/D291-34662
ISSN: 1097-0061
0749-503X
Datum des Eintrags: 8-Sep-2021
Bezeichnung des in Beziehung stehenden Objekts: Supporting Information
In Beziehung stehendes Objekt: https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fyea.3652&file=yea3652-sup-0001-Figure+S1.tiff
https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fyea.3652&file=yea3652-sup-0002-Figure+S2.tiff
https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fyea.3652&file=yea3652-sup-0003-Data+S1.docx
Fakultät: ZE - Zentrale Einrichtungen
Fachrichtung: ZE - Zentrum für Human- und Molekularbiologie (ZHMB)
Professur: ZE - Sonstige
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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