Dr. Jeffrey Brodsky

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

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

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.

Publication Archive
94 Citations
90 Abstracts
68 PDFs

Recent Publications of Jeffrey Brodsky

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

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)

Buck, T.M., C.M. Wright, and J.L. Brodsky (2007) The activities and function of molecular chaperones in the endoplasmic reticulum. Semin. Cell Dev. Biol. 18:751-761 (PDF Reprint: 393 kb)

Wright, C.M., R.J. Chovatiya, N.E. Jameson, D.M. Turner, G. Zhu, S. Werner, D.M. Huryn, J.M. Pipas, B.W. Day, P. Wipf, and J.L. Brodsky (2007) Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation. Bioorg. Med. Chem. 16:3291-3301 (PDF Reprint: 299 kb)

Feng, D., X. Zhao, C. Soromani, J. Toikkanen, K. Romisch, S.S. Vembar, J.L. Brodsky, S. Keranen, and J. Jantti (2007) The trans-membrane domain is sufficient for Sbh1p function, its association with the Sec61 complex and its interaction with Rtn1p. J. Biol. Chem. 282:30618-30628 (PDF Reprint: 584 kb)

Brodsky, J.L., and C.M. Scott (2007) Tipping the delicate balance: Defining how proteasome maturation affects the degradation of a substrate for autophagy and endoplasmic reticulum associated degradation (ERAD). Autophagy 3:623-625 (PDF Reprint: 145 kb)

Hrizo, S.L., V. Gusarova, D.M. Habiel, J.L. Goeckeler, E.A. Fisher, and J.L. Brodsky (2007) The Hsp110 molecular chaperone stabilizes apolipoprotein B from endoplasmic reticulum associated degradation (ERAD). J. Biol. Chem. 282:32665-32675 (PDF Reprint: 579 kb)

Kashlan, O.B., G.M. Mueller, M.Z. Qamar, P.A. Poland, A. Ahner, R.C. Rubenstein, R.P. Hughey, J.L. Brodsky, and T.R. Kleyman (2007) Small heat shock protein alpha A-crystallin regulates epithelial sodium channel expression. J. Biol. Chem. 282:28149-28156 (PDF Reprint: 534 kb)

Scott, C.M., K.B. Kruse, B.Z. Schmidt, D.H. Perlmutter, A.A. McCracken, and J.L. Brodsky (2007) ADD66, a gene involved in the endoplasmic reticulum associated degradation (ERAD) of alpha-1-antitrypsin-Z in yeast, facilitates proteasome activity and assembly. Mol. Biol. Cell 18:3776-3787 (PDF Reprint: 852 kb)

Rodina, A., M. Vilenchik, K. Moulick, J. Aguirre, J. Kim, A. Chiang, J. Litz, C.C. Clement, Y. Kang, Y. She, N. Wu, S. Felts, P. Wipf, J. Massague, X. Jiang, J.L. Brodsky, G.W. Krystal, and G. Chiosis (2007) Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Nat. Chem. Biol. 3:498-507 (PDF Reprint: 622 kb)

Wahlman, J., G.N. Demartino, W.R. Skach, N.J. Bulleid, J.L. Brodsky, and A.E. Johnson (2007) Real-Time fluorescence detection of ERAD substrate retrotranslocation in a mammalian in vitro system. Cell 129:943-955 (PDF Reprint: 997 kb)

Perlmutter, D.H., J.L. Brodsky, W.F. Balistreri, and B.C. Trapnell (2007) Molecular pathogenesis of alpha-1-antitrypsin deficiency-associated liver disease: A meeting review. Hepatology 45:1313-1323 (PDF Reprint: 329 kb)

Jelenska, J., N. Yao, B.A. Vinatzer, C.M. Wright, J.L. Brodsky, and J.T. Greenberg (2007) A J domain virulence effector of Pseudomonas syringae remodels host chloroplasts and suppresses defenses. Curr. Biol. 17:499-508 (PDF Reprint: 1.3 MB)

Mandal, A.K., P. Lee, J.A. Chen, N. Nillegoda, A. Heller, S. Distasio, H. Oen, J. Victor, D.M. Nair, J.L. Brodsky, and A.J. Caplan (2007) Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation. J. Cell. Biol. 176:319-328 (PDF Reprint: 1.2 MB)

Ahner, A., K. Nakatsukasa, H. Zhang, R.A. Frizzell, and J.L. Brodsky (2007) Small Heat Shock Proteins Select DF508-CFTR for ER Associated Degradation (ERAD). Mol. Biol. Cell 18:806-814 (PDF Reprint: 779 kb)

How to Contact Jeffrey Brodsky

US Mail
University of Pittsburgh
Department of Biological Sciences
274A Crawford 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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