#ER stress

Protein Sorting and Trafficking

The unfolded protein response (UPR) is triggered by:

Unfolded protein response is evolutionarily conserved stress signaling program activated when concentration of unfolded polypeptides in ER lumen exceeds buffering capacity of BiP and other chaperones, threatening proteostasis. Under basal conditions, BiP binds lumenal domains of three ER transmembrane sensors keeping them inactive: IRE1 bifunctional kinase-endoribonuclease that upon dimerization autophosphorylates and splices XBP1 mRNA removing 26 nucleotide intron producing active transcription factor inducing chaperones, lipid synthesis and ERAD genes; PERK kinase that phosphorylates eIF2α a

Ref: Walter & Ron, Science 334: 2011, UPR Triggered by Misfolded Proteins.

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Protein Sorting and Trafficking

What happens when a protein fails to fold correctly in the ER?

Inability to achieve native conformation triggers layered proteostasis network aimed at restoring balance and if impossible eliminating dangerous species. Initially, chaperone BiP binds exposed hydrophobic stretches, UGGT reglucosylates non-native N-glycoproteins returning them to calnexin-calreticulin cycle for additional attempts at oxidative folding assisted by PDI family, ERp57, Ero1 and peptidyl-prolyl isomerases. Kinetic competition with slow mannosidases EDEM1-3 acts as timer: prolonged residence leads to progressive removal of terminal mannoses preventing reglucosylation and generating

Ref: Walter & Ron, Science 334: 2011, Handling of Misfolded Proteins and UPR.

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Protein Sorting and Trafficking

Misfolded proteins in the ER are eventually:

When attempts at native conformation repeatedly fail despite chaperone assistance including BiP binding and calnexin-mediated retention plus UGGT reglucosylation cycles, terminally misfolded proteins must be removed to prevent proteotoxic aggregation, ER stress and activation of apoptotic pathways. Lumenal quality control uses mannose timer: ER mannosidase I and EDEM1-3 remove specific α1-2 mannose residues from core glycan converting Man9GlcNAc2 to Man7-6 isoforms with reduced affinity for folding lectins and increased affinity for degradation lectins. Trimmed glycans recognized by MRH domain

Ref: Ruggiano et al., Nature Rev Mol Cell Biol 15: 2014, ERAD of Misfolded Proteins.

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Protein Sorting and Trafficking

Which molecular chaperone is responsible for stabilizing unfolded proteins in the ER?

Stabilization of unfolded secretory proteins inside endoplasmic reticulum oxidizing environment depends on lectin chaperone system that monitors glycosylation status and provides time for folding. Calreticulin, soluble paralog of membrane-bound calnexin sharing lectin domain but lacking transmembrane anchor, resides in ER lumen at millimolar concentration. It binds specifically monoglucosylated Glc1Man9GlcNAc2 N-glycans generated after glucosidase I and II trimming of precursor added en bloc. Its long proline-rich P-domain arm extends to recruit oxidoreductase ERp57 forming mixed disulfides wi

Ref: Braakman & Hebert, Cold Spring Harb Perspect Biol 5: 2013, Calreticulin Chaperone Role.

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