Douglas Cyr, Ph.D.


Lab Personnel


  • B.S., Roger Williams University, 1984
  • Ph.D., University of Rhode Island, 1989
  • Postdoc, UNC-Chapel Hill, 1989-93
  • Postdoc, University of Munich, 1993-95
  • Joined the Department in 2001

Funding Sources

  • National Institutes of Health
  • Cystic Fibrosis Foundation
  • Fogarty International Center
  • American Heart Association

Research Interests

Areas of Investigation

The major research goal of the Cyr laboratory is to understand the molecular mechanisms that underlie disorders associated with protein misfolding and aggregation. We focus on Cystic Fibrosis and Huntington’s disease and seek to understand the mechanism by which molecular chaperones protect cells from the consequences of protein misfolding. Our long-term goal is to use information gained from mechanism-based approaches to identify novel therapeutic targets for small molecules that could prevent protein folding diseases.


A growing number of human disorders are caused by mutations that result in altered protein conformations. Most cases of Cystic Fibrosis are caused by mutations that lead to subtle folding defects that cause the Cl- channel CFTR to be degraded prematurely. In contrast, Huntington’s disease is caused by structural alterations in mutant Huntington’s protein that cause it to accumulate in insoluble, amyloid-like aggregates that are found inside and sometimes outside of affected cells. Molecular chaperones play a critical role in protein folding and degradation. The mechanisms by which they act in pathways that lead to Cystic Fibrosis and Huntington’s disease are being actively investigated in our laboratory.


To study protein folding diseases we utilize a broad array of modern research techniques and model systems that include animal models, mammalian cell culture, yeast and cell free systems. Studies on Cystic Fibrosis are carried out in cultured cells and seek to identify quality control factors that determine the fate of CFTR. Studies on Huntington’s disease utilize yeast and purified proteins as a model systems, which enable us to define the mechanism of Hsp40 and Hsp70 action in suppressing the proteotoxicity related to aggregation of Huntington’s protein.


Our laboratory has recently made major progress in two broad areas. We have identified two distinct chaperone machineries that function sequentially to sense the folded state of CFTR and target mutant forms for proteasomal degradation. In an attempt to rescue misfolded CFTR from degradation and cure CF, we are developing approaches to inactivate these novel QC complexes in human bronchial epithelial cells. In related studies, we utilized biophysical approaches to determine the high-resolution structure of Hsp40 chaperones. The data obtained have defined aspects of the mechanism by which Hsp40s bind and deliver non-native proteins to Hsp70. Tests of structure-based models for the mechanism by which Hsp40 and Hsp70 cooperate to modulate Huntington’s protein toxicity are in progress.

Questions Addressed in Ongoing Studies

  • How is the function of Hsp70 regulated by folding and degradatory co-chaperones?
  • How do cellular quality control factors decide whether to fold or degrade non-native CFTR?
  • How do chaperones mediate cytoprotection against Huntington's disease?
  • How does the accumulation of aberrant forms of Huntington's protein cause cell death?
  • Can the modulation of quality control pathways have a positive influence on the fate of disease related proteins?
  • Can we identify small molecules that block cellular pathways important for the etiology of protein folding diseases?


Helpful Resources

Protein Misfolding Diseases: Current and Emerging Principles and Therapies.  Wiley, New York. July 201


Selected Publications

PubMed 1

  • Meacham, G., Zhang, W., Younger J.M., Patterson, C. and Cyr, D.M. (2001) The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nature Cell Biol., 3:100-105.
  • Cyr, D.M., Hohfeld, J and Patterson, C (2002) Protein quality control: U-box containing E3 ubiquitin ligases join the fold. Trends in Biochem. Sci., 27, 368-375.
  • Fan,C, Lee,S,Ren, H. and Cyr, D.M. (2004) Exchangeable chaperone modules contribute to specification of Type I and Type II Hsp40 cellular function, Mol. Biol. Cell, 15: 761-773.
  • Younger, J.M. Ren, H-Y, Fan, C-Y, Chen., L. Patterson, C. and Cyr, D.M. (2004) A foldable CFTR∆F508 biogenic intermediate accumulates upon inhibition of the Hsc70/CHIP E3 Ubiquitin ligase complex. J. Cell Biology,167:1075-1085.
  • Fan C., Ren, H, Lee, P. Caplan, A.J., and Cyr, D.M. (2005) The Type I Hsp40 zinc finger-like domain is required for Hsp70 to capture polypeptides from Ydj1. J. Biol. Chem. 280:695-702.
  • Cyr, D.M. (2005) Arrest of CFTR∆F508 folding. Nature Struc. and Mol. Biol. 12:2-3.
  • Qian, S-B, McDonough, H., Boellmann, F., Cyr, D.M. and Patterson, C. (2006) Restitution of the stress response by hierarchical substrate-dependent autoregulation of Hsp70. Nature 440:551-5.
  • Douglas PM, Treusch S, Ren HY, Halfmann R, Duennwald ML, Lindquist S, Cyr DM. (2008) Chaperone-dependent amyloid assembly protects cells from prion toxicity. Proc Natl Acad Sci U S A, 105(20):7206-11.

  • Younger, J.M., Chen, L., Ren, H-Y, Rosser, MFN., Trunbull. E.L., Patterson, C., and Cyr, D.M. (2006) Sequential Quality Control Checkpoints Triage misfolded cystic fibrosis transmembrane conductance regulator. Cell, 126:571-82.
  • Rosser MF, Washburn E, Muchowski PJ, Patterson C, Cyr DM. (2007) Chaperone functions

    of the E3 ubiquitin ligase CHIP. J Biol Chem, 282(31):22267-77.

  • Douglas PM, Treusch S, Ren HY, Halfmann R, Duennwald ML, Lindquist S, Cyr DM. (2008) Chaperone-dependent amyloid assembly protects cells from prion toxicity. Proc Natl Acad Sci U S A, 105(20):7206-11.

  • Cyr DM. (2008) Swapping nucleotides, tuning Hsp70. Cell, 133(6):945-7.

  • Rosser MF, Grove DE, Chen L, Cyr DM. (2008) Assembly and misassembly of cystic fibrosis transmembrane conductance regulator: folding defects caused by deletion of F508 occur before and after the calnexin-dependent association of membrane spanning domain (MSD) 1 and MSD2. Mol Biol Cell, 19(11):4570-9.

  • Summers DW, Douglas PM, Ren HY, Cyr DM. (2009) The type I Hsp40 Ydj1 utilizes a farnesyl moiety and zinc finger-like region to suppress prion toxicity. J Biol Chem, 284(6):3628-39.

  • Grove DE, Rosser MF, Ren HY, Naren AP, Cyr DM. (2009) Mechanisms for rescue of correctable folding defects in CFTRDelta F508. Mol Biol Cell, 20(18):4059-69.

  • Douglas PM, Summers DW, Ren HY, Cyr DM. (2009) Reciprocal efficiency of RNQ1 and polyglutamine detoxification in the cytosol and nucleus. Mol Biol Cell, 20(19):4162-73.

  • Nillegoda NB, Theodoraki MA, Mandal AK, Mayo KJ, Ren HY, Sultana R, Wu K, Johnson J, Cyr DM, Caplan AJ. (2010) Ubr1 and ubr2 function in a quality control pathway for degradation of unfolded cytosolic proteins. Mol Biol Cell, 21(13):2102-16.