Hsp70 and DNAJA2 limit CFTR levels through degradation

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Cystic Fibrosis (CF) arises from mutations in the CFTR anion channel, often leading to protein misfolding and premature degradation.
• Hsc70/Hsp70 chaperones and DNAJA1 are crucial for CFTR folding but also implicated in its degradation, presenting a paradox.
• Understanding the balance between these opposing roles is critical for developing therapeutic strategies.

Purpose of the Study:

• To elucidate the opposing roles of Hsc70/Hsp70 chaperones and their co-chaperones in CFTR protein folding and degradation.
• To investigate how modulating Hsp70 activity impacts CFTR levels and function, particularly for the common ΔF508-CFTR variant.

Main Methods:

• Investigated the roles of DNAJA1 and DNAJA2 in CFTR folding and endoplasmic reticulum-associated degradation (ERAD).
• Examined the impact of Hsp70 overexpression and inhibition (using MKT077) on CFTR turnover via proteasomal and lysosomal pathways.
• Assessed the effect of MKT077, alone and in combination with VX809, on mature CFTR levels and ΔF508-CFTR channel activity.

Main Results:

• DNAJA2, unlike DNAJA1, enhanced CFTR degradation at the ER through Hsc70/Hsp70 and CHIP.
• Excess Hsp70 promoted lysosomal CFTR degradation, requiring CHIP but not HOP/Hsp90.
• Hsp70 inhibition with MKT077 increased mature CFTR and ΔF508-CFTR levels by reducing turnover and delaying maturation, respectively.
• MKT077 enhanced ΔF508-CFTR channel activity when combined with VX809.

Conclusions:

• The Hsp70 system is a primary regulator of CFTR degradation.
• Modulating Hsp70 activity offers a potential therapeutic approach to partially rescue the CFTR misfolding phenotype.
• Targeting Hsp70 may improve CFTR levels and function in Cystic Fibrosis patients.