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Role of Hsp105 in CFTR Biogenesis

Saxena, Anita

Abstract Details

2010, Doctor of Philosophy in Biomedical Sciences (Ph.D.), University of Toledo, College of Medicine.
Cystic fibrosis (CF) is a life-threatening genetic disease arising from mutations in the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). The mutant ΔF508 CFTR accounts for more than 70% of the CF causing alleles and exhibits temperature sensitive export defect from the endoplasmic reticulum (ER). Hsp105/110 facilitates the nucleotide exchange of Hsp70 and possesses independent chaperone activity (holdase activity) in vitro. Human Hsp105α, the constitutively expressed isoform, has been shown to associate with CFTR in the ER but its role in CFTR biogenesis is as yet unclear. We show that Hsp105 plays versatile roles in CFTR biogenesis in the ER affecting synthesis, maturation and degradation. The nucleotide exchange activity of Hsp105 is necessary for the degradation of CFTR in the ER. Its holdase activity reduces synthesis and stabilizes CFTR in the ER. Hsp105 stabilizes CFTR in the ER and proportionally promotes its processing. Hsp105 preferentially associates with ΔF508 CFTR and promotes its stabilization and rescue at both reduced and physiological temperatures. In addition, Hsp105 escorts the mutant CFTR in post-ER compartments and prolongs its half-life. Hsp105’s versatile functions and its high affinity for misfolded ΔF508 CFTR make it a useful molecular target for the rescue of protein misfolding in CF. Hsp70 and Hsp90 regulate CFTR biogenesis but their functional relationship remains unknown. Using the temperature-dependent rescue of ΔF508 CFTR as a model system we provide evidence for functional cooperation between Hsp70 and Hsp90 mediated by cochaperones Hop and Hsp105 in conformational maturation in the ER. Hsp70 associates with ΔF508 CFTR earlier than Hsp90. Hsp90 directly promotes its maturation and the integrity of Hsp70-Hsp90 chaperone network is essential for maturation of ΔF508 CFTR at reduced temperature. Our data support Hsp105 as an integral player in the Hsp70-Hsp90 chaperone network mediated CFTR conformational maturation in the ER.
Xiaodong Robert Wang, Ph.D. (Committee Chair)
Andrew Beavis, Ph.D. (Committee Member)
Bina Joe, Ph.D. (Committee Member)
David Giovannucci, Ph.D. (Committee Member)
William Maltese, Ph.D. (Committee Member)
226 p.

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Citations

  • Saxena, A. (2010). Role of Hsp105 in CFTR Biogenesis [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1279120195

    APA Style (7th edition)

  • Saxena, Anita. Role of Hsp105 in CFTR Biogenesis. 2010. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1279120195.

    MLA Style (8th edition)

  • Saxena, Anita. "Role of Hsp105 in CFTR Biogenesis." Doctoral dissertation, University of Toledo, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=mco1279120195

    Chicago Manual of Style (17th edition)