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The Nucleotide Exchange Factor Sil1 Modulates Redox Signaling through the Molecular Chaperone BiP
Author(s) -
Siegenthaler Kevin,
Pareja Kristeen,
Wang Jie,
Sevier Carolyn
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.773.2
Subject(s) - endoplasmic reticulum , chaperone (clinical) , chemistry , unfolded protein response , oxidative folding , microbiology and biotechnology , biochemistry , cysteine , calnexin , protein folding , sulfenic acid , protein disulfide isomerase , atp hydrolysis , chemical chaperone , proteostasis , atpase , calreticulin , biology , enzyme , medicine , pathology
The endoplasmic reticulum (ER) is responsible for the secretion of approximately one third of the eukaryotic proteome. The oxidizing environment within the ER lumen allows for the formation of disulfide bonds present in many secreted proteins. However, oxidative protein folding generates hydrogen peroxide, which can over oxidize the ER and disrupt protein folding. Since protein flux through the ER can vary widely in a cell depending on developmental phase and environmental factors, the oxidative status of the organelle can fluctuate. It is critical that cells maintain the fidelity of protein folding despite the fluctuating redox environment. One way cells do this is by regulating the activity of the lumenal Hsp70 chaperone, BiP. When hydrogen peroxide accumulates in the ER, a conserved cysteine residue in BiP is oxidized to cysteine sulfenic acid. This decouples the normally ATPase driven chaperones nucleotide hydrolysis cycle from its peptide binding, resulting in constitutively higher peptide binding by the chaperone. BiP therefore tightly binds translocating proteins and maintains them in a folding‐competent state until oxidative stress levels subside. While BiP oxidation is protective during periods of oxidative stress, constitutive modification decreases cell fitness, raising the question of how BiP is reduced post stress. Unexpectedly, we have found that Sil1, one of BiP's nucleotide exchange factors, is able to reduce BiP and restore progression through the chaperones ATPase cycle. Sil1's reductase activity is tractable to a catalytic cysteine pair near the proteins N‐terminus and is distinct from its activity as a NEF. We are currently studying the role Sil1's reducing activity plays in the cells oxidative stress response and how this connects to human health. Interestingly, mutations in the Sil1 gene are associated with the cerebellar ataxia Marinesco Sjögren syndrome (MSS), suggesting loss of Sil1's reducing activity may cause ER dysfunction that manifests itself in a multi‐system disorder. Support or Funding Information R01 GM105958 T32 GM007273