Carolyn S. Sevier
Assistant Professor

Carolyn S. Sevier




Department of Molecular Medicine
C4-141 Veterinary Medical Center
College of Veterinary Medicine
Cornell University
Ithaca, New York 14853-2703


Web Sites

Lab Website


Normal cell function relies on an ability of the ER to efficiently fold proteins. The crucial role of protein folding for cellular function is underscored by the number of diseases associated with the defective maturation of ER-generated polypeptides. An essential step in the folding of many proteins within the ER lumen is the formation of disulfide bonds between cysteine residues. Disulfide bond formation in proteins relies on a proper redox environment and oxidative folding in the ER is acutely sensitive to perturbation of the lumenal ER environment. My studies have revealed an unexpected role for the chaperone BiP (a member of the Hsp70 ATPase family) in coping with potentially detrimental redox alterations within the ER lumen. This BiP-centric cellular response to ER oxidative stress is mechanistically distinct from previously characterized ER stress responses and involves redox signaling via a conserved cysteine residue in BiP. Modification of BiP and alteration of its normal cellular function appears to be a physiological mechanism used to signal a redox imbalance within the ER and allow the ER to cope with an existing misoxidized substrate load. Research in my lab focuses on further defining this redox-signaling pathway within the ER. Mechanistic studies of the BiP-centric pathway in the ER in the lab will be complemented by more general proteomics approaches to identify new redox signaling pathways involving other ER resident proteins.

Research Description

My research interests focus on characterizing cellular pathways that sense and signal redox imbalances within the cell to alleviate oxidative stress. Specifically, research efforts in my lab focus on how the cell maintains a redox environment in the endoplasmic reticulum (ER) lumen appropriate for oxidative protein folding. We study the molecular mechanisms regulating cellular oxidative folding and stress pathways using a combination of molecular, genetic, and biochemical techniques.


Heldman, N., Vonshak, O., Sevier, C.S., Vitu, E., Mehlman, T., and Fass, D. 2010. Steps in reductive activation of the disulfide-generating enzyme Ero1p. Protein Science 19:1863-1876.

Vitu, E., Kim, S., Sevier, C.S., Lutzky, O., Heldman, N., Bentzur, M., Unger, T., Yona, M., Kaiser, C.A., and Fass, D. 2010. Oxidative activity of yeast Ero1p on protein disulfide isomerase and related oxidoreductases of the endoplasmic reticulum. J. Biol. Chem. 285:18155-18165.

Sevier, C.S. 2010. New insights into oxidative folding. J. Cell Biol. 188:757-758.

Costanzo, M., Baryshnikova, A., Bellay, J., Kim, Y., Spear, E.D., Sevier, C.S., Ding, H., Koh, J.L.Y, Toufighi, K., Mostafavi, S., Prinz, J., St. Onge, R.P., VanderSluis, B., Alizadeh, S., Bahr, S., Brost, R.L., Chen, Y., Cokol, M., Deshpande, R., Li, Z., Li, Z-Y., Liang, W., Marback, M., Paw, J., San Luis, B-J., Shuteriqi, E., Tong, A.H.Y., van Dyk, N., Wallace, I.M., Whitney, J.A., Weirauch, M.T., Zhong, G., Zhu, H., Houry, W.A., Brudno, M., Ragibizadeh, S., Papp, B., Roth, F.P., Giaever, G.N., Nislow, C., Troyanskaya, O.G., Bussey, H., Bader, G.D., Gingras, A.C., Morris, Q.D., Kim, P.M., Kaiser, C.A., Myers, C.L., Andrews, B.J., Boone, C. 2010. The Genetic Landscape of a Cell. Science 327: 425-431.

Fass, D. and Sevier, C.S. 2009. The Ero1 sulfhydryl oxidase and the oxidizing potential of the endoplasmic reticulum in Oxidative Folding of Peptides and Proteins. Moroder, L. and Buchner, J. (Eds), Royal Society of Chemistry.

Vitu, E., Gross, E., Greenblatt, H, Sevier, C.S., Kaiser, C.A., and Fass, D. 2008. Yeast Mpd1p reveals the structural diversity of the protein disulfide isomerase family. J. Mol. Biol. 384:631-640.

Sevier, C.S., and Kaiser, C.A. 2008. Ero1 and redox homeostasis in the endoplasmic reticulum. BBA - Molecular Cell Research 1783: 549-556.

Sevier, C.S., Qu, H., Heldman, N., Gross, E., Fass, D., and Kaiser, C.A. 2007. Modulation of cellular disulfide bond formation and the ER redox environment by feedback regulation of Ero1. Cell 129:333-344.

Sevier, C.S., and Kaiser, C.A. 2006. Conservation and diversity of the cellular disulfide bond formation pathways. Antioxid. Redox Signal. 8: 797-811.

Sevier, C.S., and Kaiser, C.A. 2006. Disulfide transfer between two conserved cysteine pairs imparts selectivity to protein oxidation by Ero1. Mol. Biol. Cell 17:2256-2266.

Gross, E., Sevier, C.S., Heldman, N., Vitu, E., Kaiser, C.A., Thorpe, C., and Fass D. 2006. Generating disulfides in the endoplasmic reticulum: reaction products and alternate electron acceptors for Ero1p. Proc. Natl. Acad. Sci. 103:299-304.

Vala, A., Sevier, C.S., and Kaiser, C.A. 2005. Structural determinants of substrate access to the disulfide oxidase Erv2p. J. Mol. Biol. 354:952-66.

Sevier, C.S., Kadokura, H., Tam, V.C., Beckwith, J., Fass, D., and Kaiser, C.A. 2005. The prokaryotic enzyme DsbB may share key structural features with eukaryotic disulfide bond forming oxidases. Protein Science 14:1630-1642.

Sevier, C.S., and Kaiser, C.A. 2002. Formation and transfer of disulphide bonds in living cells. Nature Rev. Mol. Cell Biol. 3: 836-847.

Gross, E., Sevier, C.S., Vala, A., Kaiser, C.A., and Fass, D. 2002. New FAD-binding fold and intersubunit disulfide shuttle in the thiol oxidase Erv2p. Nature Struct. Biol. 9: 61-67.

Sevier, C.S., Cuozzo, J.W., Vala, A., Aslund, F., and Kaiser, C.A. 2001. A flavoprotein oxidase defines a new endoplasmic reticulum pathway for biosynthetic disulphide bond formation. Nature Cell Biol. 3: 874-882.

Sevier, C.S., and Machamer, C.E. 2001. p38: a novel protein that associates with the vesicular stomatitis virus glycoprotein. Biochem. Biophys. Res. Commun. 287: 574-582.

Sevier, C.S., Cuozzo, J.W., Vala, A., Aslund, F., and Kaiser, C.A. 2001. A flavoprotein oxidase defines a new endoplasmic reticulum pathway for biosynthetic disulphide bond formation. Nature Cell Biol. 3: 874-882.

Sevier, C.S., Weisz, O.A., Davis, M., and Machamer, C.E. 2000. Efficient export of the vesicular stomatitis virus G protein from the endoplasmic reticulum requires a signal in the cytoplasmic tail that includes both tyrosine-based and di-acidic motifs. Mol. Biol. Cell 11: 13-22.

Sevier, C.S., and Machamer, C.E. 1998. Fragmentation of a Golgi-localized chimeric protein allows detergent solubilization and reveals an alternate conformation of the cytoplasmic domain. Biochemistry 37: 185-192.

Fann, M., Davies, A.H., Varadhachary, A., Kuroda, T., Sevier, C., Tsuchiya, T., and Maloney, P.C. 1998. Identification of two essential arginine residues in UhpT, the sugar phosphate antiporter of Escherichia coli. J. Membr. Biol. 164: 187-195.