Orchestration of secretory protein folding by ER chaperones

Abstract

The endoplasmic reticulum is a major compartment of protein biogenesis in the cell, dedicated to production of secretory, membrane and organelle proteins. The secretome has distinct structural and post-translational characteristics, since folding in the ER occurs in an environment that is distinct in terms of its ionic composition, dynamics and requirements for quality contol. The folding machinery in the ER therefore includes chaperones and folding enzymes that introduce, monitor and react to disulfide bonds, glycans, and fluctuations of luminal calcium. We describe the major chaperone networks in the lumen and discuss how they have distinct modes of operation that enable cells to accomplish highly efficient production of the secretome.

Transit of H2O2 across the endoplasmic reticulum membrane is not sluggish

“…By contrast, depletion of the ER-luminal high-abundance-high-affinity-high-turnover-peroxidase peroxiredoxin 4 [40,41] does not cause similar leakage of Ero1 -derived H 2 O 2 into the cytosol [39]. Thus, the shielding of the cytosol against Ero1 -derived H 2 O 2 takes place at the Ero1 -GPx8 interface through catalytic elimination [42].…”

Redox controls UPR to control redox

“…This control function has originally been ascribed to PrxIV (Tavender and Bulleid, 2010), but more recent findings suggest that (i) the GPX enzymes specifically reduce Ero1-derived H 2 O 2 and that (ii) PrxIV targets an alternative source of H 2 O 2 in the ER (Ramming et al, 2014). In most disulfide-generating pathways in the ER, members of the PDI family serve as the primary disulfide acceptor (Appenzeller-Herzog and Ellgaard, 2008;Gidalevitz et al, 2013). PDIs, in turn, can oxidize cysteine residues on substrates to mediate oxidative folding.…”

“…As a prerequisite for such communication, eukaryotic cells developed a specialized endomembrane system known as the secretory pathway, in which peptide hormones, membrane receptors and other secretory cargo proteins are synthesized, folded and eventually released to the extracellular space. The endoplasmic reticulum (ER), where translation and folding of extracellular proteins occurs, is the first component of the secretory pathway (Gidalevitz et al, 2013). When ER homeostasis is compromised, a set of 'ER stress' signals is transmitted to the cytoplasm and nucleus.…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…The ER is an extensive intracellular membrane network that extends throughout the cytoplasm and is essential for the translation and folding of membrane and secretory proteins (Gidalevitz et al, 2013). It is also a critical site of lipid and glucose metabolism, calcium homeostasis, and detoxification of drugs and metabolic byproducts.…”