Regulation of degradation of wt-CFTR (norm)
The cystic fibrosis transmembrane conductance regulator ( CFTR ) is a member of the ATP-binding cassette transporter superfamily. It acts in the apical part of the epithelial cells as a plasma-membrane cyclic AMP-activated chloride anion, bicarbonate anion and glutathione channel , , . Cell surface expression of the CFTR is a highly regulated intracellular process , .
Two ubiquitin ligase complexes mark wt-CFTR for degradation - ER ubiquitin ligase complex and cytosolic ubiquitin ligase complex. The first complex (ER membrane-associated ubiquitin ligase complex) contains the E3 RMA1 ( RNF5 ), the E2 Ubc6e ( UNE2J1 ), and Derlin-1. Derlin-1 interacts with nonubiquitylated CFTR and serves to retain CFTR in the ER membrane , .
Cochaperone HspBP1 is an inhibitor of CHIP. HspBP1 attenuates the ubiquitin ligase activity of CHIP when complexed with Hsc70. As a consequence, HspBP1 interferes with the CHIP-induced degradation of immature forms and may modulate the function of the Hsc70/CHIP complex .
Csp ( DnaJ (Hsp40) homolog, subfamily C, member 5) , blocks ER exit of wt-CFTR. Additionally, Csp associates with CHIP and facilitates degradation of immature wt-CFTR (Schmidt, B. unpublished data, The 21 st Annual North American CF conference Anaheim Convention Center, Anaheim, California, October 3-6, 2007}
The ubiquitylated wt-CFTR is transported through the Sec61 trimeric complex back to the cytosol, escorted by the beta subunit of Sec61 .
VCP/p97, a Type II AAA ATPase component of the retrotranslocation machinery, forms a complex with substrate-recruiting cofactors Ufd1/Npl4. VCP binds polyubiquinated wt-CFTR while Ufd1/Npl4 interacts to the ubiquitin chains on the substrate , . VCP activity may be regulated by Ataxin-3 .
In situations where 26S proteasome are compromised or overwhelmed, ubiquitinated misfolded wt-CFTR is transported to a perinuclear location near the microtubule-organizing center to form aggresomes , .