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REDOX SIGNALING THROUGH THE ENDOPLASMIC RETICULUM CHAPERONE BIP

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dc.contributor.authorSiegenthaler, Kevin David
dc.contributor.chairSevier, Carolyn S.
dc.contributor.committeeMemberHelmann, John D.
dc.contributor.committeeMemberBrown, William J.
dc.date.accessioned2019-10-15T15:28:50Z
dc.date.available2021-06-05T06:00:26Z
dc.date.issued2019-05-30
dc.description.abstractThe process of oxidative protein folding in the endoplasmic reticulum (ER) generates hydrogen peroxide, a reactive oxygen species (ROS). The secretory load of a cell can vary widely, and cells require mechanisms to maintain folding fidelity within the ER despite fluctuating ROS levels. One such mechanism involves tuning the activity of the ER Hsp70 chaperone, BiP. Our lab established that a conserved cysteine residue within the nucleotide-binding domain of S. cerevisiae BiP (Kar2) is oxidized in response to ROS accumulation, and oxidation causes the chaperone to bind peptides with perpetually high affinity. The modified peptide-binding activity of oxidized BiP imparts a protective advantage to cells during oxidative stress by limiting aggregation of proteins damaged by ROS. Although beneficial when ROS levels are high, perpetual BiP modification and the holding of peptides decreases cell fitness under non-stressed conditions. Thus, it is essential that cells coordinate BiP oxidation to maintain folding homeostasis with the changing ER redox status. Here we uncover roles for the BiP nucleotide exchange factor, Sil1, and the oxidative protein folding enzyme, protein disulfide isomerase (PDI), in controlling the redox state of BiP In Chapter 2, we show that Sil1 possesses a N-terminal cysteine pair capable of reducing the redox-sensitive BiP cysteine. The unexpected reductant activity of Sil1 enables BiP to resume its non-stressed peptide binding activities. In Chapter 3, we identify PDI as a further regulator of BiP oxidation as PDI reduces BiP both directly and by providing electrons to activate Sil1. Due to its role in oxidative protein folding, the redox state of PDI (and its capacity to give electrons to BiP) is tightly linked to the current redox status of the ER. We suggest that together PDI and Sil1 serve as sensors of the ER redox state that adjust BiP function to match the ER redox status.
dc.identifier.doihttps://doi.org/10.7298/9fam-y122
dc.identifier.otherSiegenthaler_cornellgrad_0058F_11351
dc.identifier.otherhttp://dissertations.umi.com/cornellgrad:11351
dc.identifier.otherbibid: 11050249
dc.identifier.urihttps://hdl.handle.net/1813/67267
dc.language.isoen_US
dc.subjectSil1
dc.subjectCellular biology
dc.subjectBiochemistry
dc.subjectBiP
dc.subjectEndoplasmic reticulum
dc.subjectOxidative Stress
dc.subjectPDI
dc.titleREDOX SIGNALING THROUGH THE ENDOPLASMIC RETICULUM CHAPERONE BIP
dc.typedissertation or thesis
dcterms.licensehttps://hdl.handle.net/1813/59810
thesis.degree.disciplineBiochemistry, Molecular and Cell Biology
thesis.degree.grantorCornell University
thesis.degree.levelDoctor of Philosophy
thesis.degree.namePh.D., Biochemistry, Molecular and Cell Biology

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