Syntaxin 8 and the Endoplasmic Reticulum Processing of ΔF508-CFTR
| Autor: | Clément Boinot, Inna Sabirzhanova, William B. Guggino, Liudmila Cebotaru |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cystic Fibrosis Physiology Endosome Immunoprecipitation SUMO protein Cystic Fibrosis Transmembrane Conductance Regulator Processing Endoplasmic Reticulum lcsh:Physiology Article Cell Line lcsh:Biochemistry 03 medical and health sciences Degradation Syntaxin Humans lcsh:QD415-436 Gene Silencing CFTR ΔF508 lcsh:QP1-981 Snare Chemistry Qa-SNARE Proteins Endoplasmic reticulum Mutant Transmembrane protein Cell biology Protein Transport 030104 developmental biology Proteolysis Protein folding |
| Zdroj: | Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology Cellular Physiology and Biochemistry, Vol 51, Iss 3, Pp 1489-1499 (2018) |
| ISSN: | 1421-9778 1015-8987 |
| Popis: | Background/Aims: Cystic fibrosis (CF) is a lethal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR). ΔF508, the most common mutation, is a misfolded protein that is retained in the endoplasmic reticulum and degraded, precluding delivery to the cell surface [1]. Methods: Here we use a combination of western blotting, immunoprecipitation, and short circuit current techniques combined with confocal microscopy to address whether the SNARE attachment protein, STX8 plays a role in ΔF508’s processing and movement out of the ER. Results: Although the SNARE protein STX8 is thought to be functionally related and primarily localized to early endosomes, we show that silencing of STX8, particularly in the presence of the Vertex corrector molecule C18, rescues ΔF508-CFTR, allowing it to reach the cell surface and increasing CFTR-dependent chloride currents by approximately 2.5-fold over control values. STX8 silencing reduced the binding of quality control protein, Hsp 27, a protein that targets ΔF508-CFTR for sumoylation and subsequent degradation, to ΔF508-CFTR. STX8 silencing increased the levels of Hsp 60 a protein involving in early events in protein folding. Conclusion: STX8 knockdown creates an environment favorable for mature ΔF508 to reach the cell surface. The data also suggest that when present at normal levels, STX8 functions as part of the cell’s quality control mechanism. |
| Databáze: | OpenAIRE |
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