Dr. Jeffrey Brodsky

Genetics
K. Arndt
T.-L. Ashman
G. Campbell
D. Chapman
G. Hatfull
J. Hildebrand
L. Jacobson
S. Kalisz
J. Martens
W. Saunders
B. Stronach
S. Tonsor
R. Wood

Microbiology
J. Boyle
G. Hatfull
R. Hendrix
J. Lawrence
J. Pipas
M. Popa
R.L. Duda
S. Godfrey
V. Oke

Molecular Biology
K. Arndt
J. Franzen
P. Grabowski
G. Hatfull
R. Hendrix
L. Jen-Jacobson
J. Martens
C. Peebles
J. Pipas
J. Rosenberg
A. Schwacha
C. Walsh

Plant Biology
T.-L. Ashman
W. Carson
S. Kalisz
V. Oke
C. Partanen
S. Tonsor
B. Traw

Science Education
A. Bledsoe
K. Curto
L. Daniels
S. Godfrey
N. Kaufmann
C. LaFave
J. Newman
E. Polinko
M. Popa
L. Roberts
T. Seiflein
R. Sherwin
A. Slinskey Legg

Structural Biology
M. Grabe
J. Hempel
R. Hendrix
L. Jen-Jacobson
J. Rosenberg
A. VanDemark

Former Faculty

Photo of Dr.
Brodsky

Mechanism and Action of Molecular Chaperones

Professor, Avinoff Chair of Biological Sciences

Dr. Brodsky received his Ph.D. in 1990 with Guido Guidotti at Harvard University, performed his postdoctoral studies with Randy Schekman at the University of California, Berkeley, and joined the Department in 1994.

Currently, Dr. Brodsky is accepting graduate students in his laboratory. Dr. Brodsky is accepting undergraduate researchers, and does sponsor students in other laboratories.

Professional Interests - Publications - Contact Information - Lab Personnel

Professional Interests of Jeffrey Brodsky

GFP expressed in yeast All secreted proteins, and most that ultimately reside within the cell, must traverse the secretory pathway, a network of intracellular organelles housing the "machines" that help secreted proteins mature. Critical components of these machines are a class of proteins known as molecular chaperones, some of which are associated with the endoplasmic reticulum (ER). However, if protein folding is inefficient or slow, a secreted protein may be targeted for destruction by a process we termed ER associated protein degradation (ERAD). During ERAD, proteins are selected as being defective and then degraded by the proteasome, a massive (~2 mDa) multi-catalytic protease that resides in the cytoplasm. Molecular chaperones may be required for ERAD by "deciding" whether a protein is sufficiently mature to transit through the secretory pathway; molecular chaperones may also direct these ERAD substrates to the proteasome. The importance of understanding the molecular mechanism of ERAD and molecular chaperone action is underscored by the fact that several human diseases-including cystic fibrosis, heart and liver disease, diabetes, and neurodegenerative diseases-can arise from defects in chaperone-mediated folding of secreted proteins and/or the ERAD pathway.

For our studies, the Brodsky laboratory utilizes a model eukaryotic organism, the yeast Saccharomyces cerevisiae. Yeast possess the same intracellular membrane organization and molecular chaperones as human cells but are amenable to rapid genetic analysis. Recent research in the Brodsky laboratory is currently directed toward understanding how molecular chaperones in the ER and the cytoplasm facilitate ERAD and protein folding in the cell. Both endogenous proteins and human proteins expressed heterologously in yeast are being examined as substrates for ERAD and chaperone-mediated folding, and data derived from our genetic studies are complemented by biochemical assays that recapitulate specific aspects of these processes. More recently, because of the connection between molecular chaperone function and human disease, we have begun to identify and screen for small molecules that affect chaperone activity, and to use proteomic and genomic attacks to identify additional components that facilitate ERAD.

Students may find the Metabolic Pathways and Regulation (BIOSC1820) Course Website useful.

Publication Archive
106 Citations
102 Abstracts
80 PDFs

Recent Publications of Jeffrey Brodsky

Vembar, S.S., Y. Jin, J.L. Brodsky, and L.M. Hendershot (2009) The mammalian Hsp40 ERdj3 requires its Hsp70 interaction and substrate-binding properties to complement various yeast Hsp40-dependent functions. J. Biol. Chem. 284:32462-32471 (PDF Reprint: 3.1 MB)

Haney, C.M., C. Schneider, B. Beck, J.L. Brodsky, and A. Domling (2009) Identification of Hsp70 modulators through modeling of the substrate binding domain. Bioorg Med Chem Lett 19:3828-3831 (PDF Reprint: 551 kb)

Brodsky, J.L., and R.J. Wojcikiewicz (2009) Substrate-specific mediators of ER associated degradation (ERAD). Curr Opin Cell Biol 21:516-521 (PDF Reprint: 495 kb)

Park, H.J., M. Mylvaganum, A. McPherson, S.W. Fewell, J.L. Brodsky, and C.A. Lingwood (2009) A soluble sulfogalactosyl ceramide mimic promotes Delta F508 CFTR escape from endoplasmic reticulum associated degradation. Chem Biol 16:461-470 (PDF Reprint: 837 kb)

Chiang, A.N., J.C. Valderramos, R. Balachandran, R.J. Chovatiya, B.P. Mead, C. Schneider, S.L. Bell, M.G. Klein, D.M. Huryn, X.S. Chen, B.W. Day, D.A. Fidock, P. Wipf, and J.L. Brodsky (2009) Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum. Bioorg. Med. Chem. 17:1527-1533 (PDF Reprint: 285 kb)

Patham, B., J. Duffy, A. Lane, R.C. Davis, P. Wipf, S.W. Fewell, J.L. Brodsky, and K. Mensa-Wilmot (2009) Post-translational import of protein into the endoplasmic reticulum of a trypanosome: an in vitro system for discovery of anti-trypanosomal chemical entities. Biochem. J. 419:507-517

Wright, C.M., S.P. Seguin, S.W. Fewell, H. Zhang, C. Ishwad, A. Vats, C.A. Lingwood, P. Wipf, E. Fanning, J.M. Pipas, and J.L. Brodsky (2009) Inhibition of Simian Virus 40 replication by targeting the molecular chaperone function and ATPase activity of T antigen. Virus Res. 141:71-80 (PDF Reprint: 778 kb)

Rabu, C., P. Wipf, J.L. Brodsky, and S. High (2008) A precursor-specific role for Hsp40/Hsc70 during tail-anchored protein integration at the endoplasmic reticulum. J. Biol. Chem. 283:27504-27513 (PDF Reprint: 743 kb)

Brodsky, J.L., and E.A. Fisher (2008) The many intersecting pathways underlying apolipoprotein B secretion and degradation. Trends Endocrinol. Metab. 19:254-259 (PDF Reprint: 339 kb)

Vembar, S.S., and J.L. Brodsky (2008) One step at a time: endoplasmic reticulum-associated degradation. Nat. Rev. Mol. Cell Biol. 9:944-957 (PDF Reprint: 1.1 MB)

Kang, Y., T. Taldone, C.C. Clement, S.W. Fewell, J. Aguirre, J.L. Brodsky, and G. Chiosis (2008) Design of a fluorescence polarization assay platform for the study of human Hsp70. Bioorg. Med. Chem. Lett. 18:3749-3751 (PDF Reprint: 217 kb)

Goeckeler, J.L., A.P. Petruso, J. Aguirre, C.C. Clement, G. Chiosis, and J.L. Brodsky (2008) The yeast Hsp110, Sse1p, exhibits high-affinity peptide binding. FEBS Lett. 582:2393-2396 (PDF Reprint: 98 kb)

Nakatsukasa, K., and J.L. Brodsky (2008) The recognition and retrotranslocation of misfolded proteins from the endoplasmic reticulum. Traffic 17:1614-1626 (PDF Reprint: 296 kb)

Tonsor, S.J., C. Scott, I. Boumaza, T.R. Liss, J.L. Brodsky, and E. Vierling (2008) Heat shock protein 101 effects in A. thaliana: genetic variation, fitness and pleiotropy in controlled temperature conditions. Mol. Ecol. 17:1614-1626 (PDF Reprint: 717 kb)

Nakatsukasa, K., G. Huyer, S. Michaelis, and J.L. Brodsky (2008) Dissecting the ER-Associated Degradation of a Misfolded Polytopic Membrane Protein. Cell 132:101-112 (PDF Reprint: 1.9 MB)

How to Contact Jeffrey Brodsky

US Mail
University of Pittsburgh
Department of Biological Sciences
A321 Langley Hall
4249 Fifth Avenue
Pittsburgh, PA 15260

Phone, FAX, Internet
Office : (412) 624-4831
Lab : (412) 624-4830
FAX : (412) 624-4759
Email : jbrodsky+@pitt.edu
Web :

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