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The Nucleotide Exchange Factor Sil1 Modulates Redox Signaling through the Molecular Chaperone BiP

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.