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1. Introduction
2. CFTR protein and its mutations in CF patients
3. Mislocalization of deltaF508 CFTR
4. Consequences of defects in CFTR function
5. CFTR activity correlates with CF severity
6. Cystic fibrosis foundation therapeutics pipeline
7. CF and CFTR folding/degradation
8. Role of chaperones in CFTR biogenesis
9. Results of calnexin inactivation
10. Results of Hsc70 inactivation
11. Regulation of Hsp70 function by Hsp40
12. Type I Hsp40 proteins contain a CAAX box
13. Steps in the CFTR folding pathway
14. Does Hsc70 facilitate CFTR degradation?
15. U-box family
16. Results of CHIP overexpression
17. CHIP expression blocks CFTR processing
18. CHIP mediated triage of misfolded proteins
19. CFTR-deltaF508 partitioning between pathways
20. RMA1 is an ER localized RING E3
21. Elevation of Rma1 levels blocks CFTR folding
22. Results of Rma1 and Ubc6e reduction
23. E2/E3 ubiquitin ligase senses folded CFTR
24. Derlin-1 protein
25. Results of DER1 overexpression
26. Results of DER1 knockdown
27. Possible role of DER1
28. CFTR-deltaF508 sensitivity to Rma1 changes
29. Regions recognized by Rma1 and CHIP E3
30. Sensing delta-F508 folding defects
31. CFTR sub-domains recognition by Rma1/CHIP
32. Small molecules and CFTR folding efficiency
33. Results of treatment with VRT-532 and Corr4a
34. Recognition of CFTR-deltaF508 folding defects
35. Acknowledgements

Topics Covered

• Cystic fibrosis is a fatal homozygous recessive disorder
• Caused primarily by misfolding of mutant forms of cystic fibrosis transmembrane conductance regulator (CFTR)
• The folding defects in mutant CFTR are detected by protein quality control machines in the endoplasmic reticulum that target mutant CFTR for premature degradation
• Small molecules that are being developed as drugs to treat cystic fibrosis enable mutant CFTR to avoid recognition by the endoplasmic reticulum quality control system and function at the cell surface

Links

Series:

• Molecular Chaperones

Categories:

• Biochemistry
• Cell Biology
• Clinical Practice

Therapeutic Areas:

• Immunology & Inflammation
• Respiratory Diseases

Talk Citation

Publication History

• Published on October 1, 2007

Financial Disclosures

• Prof. Douglas M. Cyr has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.