Regulation of degradation of wt-CFTR

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 [1], [2], [3]. Cell surface expression of the CFTR is a highly regulated intracellular process [4], [5].

Ubiquitin-proteasome-mediated degradation is the key pathway in wt-CFTR regulation [6], [7], [8], [9].

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 [10], [11].

The second complex (cytosolic ubiquitin ligase complex) contains E3 CHIP, UBCH5a and acts in Hsc70 [10], [12].

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 [13].

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 Additionally, Csp associates with CHIP and facilitates degradation of immature wt-CFTR (Schmidt, B. unpublished data, The 21^st Annual North American CF conference Anaheim Convention Center, Anaheim, California, October 3-6, 2007}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 [14].

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 [9], [15]. VCP activity may be regulated by Ataxin-3 [16].

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 [17], [18].

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