Human Heat Shock Protein 105/110 kDa (Hsp105/110) Regulates Biogenesis and Quality Control of Misfolded Cystic Fibrosis Transmembrane Conductance Regulator at Multiple Levels

Abstract

Background: Hsp105 prevents protein aggregation, accelerates Hsc70 nucleotide exchange, and functionally relates to Hsp90. Results: Hsp105 facilitates CFTR quality control coincident with translation, enhances its post-translational folding, and stabilizes misfolded CFTR at cell periphery. Conclusion: Hsp105 is a versatile regulator in CFTR folding and quality control. Significance: Hsp105 plays distinct roles in CFTR folding from other Hsc70 nucleotide exchange factors.

Hierarchical Functional Specificity of Cytosolic Heat Shock Protein 70 (Hsp70) Nucleotide Exchange Factors in Yeast

“…Sse1 has been previously shown to have a role in protein refolding in vitro and in vivo and in de novo folding in vivo (11,12). Human Hsp105 (Hsp110) has been shown to be important in CFTR folding in vivo (54). Roles of the other NEFs have not been fully investigated.…”

Binding of Human Nucleotide Exchange Factors to Heat Shock Protein 70 (Hsp70) Generates Functionally Distinct Complexes in Vitro

“…For example, none of the combinations that included Hsp105 were able to fold luciferase in our assays, suggesting that it may assist Hsp70 with other functions, such as cystic fibrosis conductance receptor trafficking and quality control (75). On the basis of this idea, it is intriguing to speculate that an impressive number of permutations might be generated by combinatorial assembly of human cochaperones.…”

“…However, members of the Hsp110 family lack the ability to refold clients (72,73), and, rather, they have a prominent NEF function on Hsp70s (41,74). Recently, human Hsp110 (termed Hsp105) has been shown to help coordinate stabilization of the cystic fibrosis conductance receptor (75), suggesting that this NEF function might be functionally important. However, there is little known about the biochemistry of Hsp105 and its relative position in the hierarchy of eukaryotic NEFs.…”

Interference with Ubiquitination in CFTR Modifies Stability of Core Glycosylated and Cell Surface Pools

“…The heat shock 70-kDa protein family and related cochaperones regulate biogenesis and quality control of CFTR (8)(9)(10), and both wildtype and common mutated forms of CFTR are degraded by ubiquitin-mediated proteasomal degradation (8,9). CFTR peripheral quality control occurs after the Golgi compartment, where CFTR localized to the cell surface undergoes endocytosis and recycling by a ubiquitin-dependent endosomal sorting system.…”

“…We showed that imposing monoubiquitination on wild-type (wt) and F508del CFTR leads to increased preservation of band B core glycosylated CFTR (7). Ubiquitination of CFTR is important for its regulation and quality control process (8)(9)(10), including ubiquitin-mediated proteasomal degradation (8,9) and recycling (11,12). However, the ubiquitination sites on wt CFTR, mechanism of degradation, and regulation of recycling are largely unknown.…”