Abstract
The endoplasmic reticulum (ER) is the major site of membrane biogenesis in most eukaryotic cells. As the entry point to the secretory pathway, it handles more than 10,000 different secretory and membrane proteins. The insertion of proteins into the membrane, their folding, and ER exit are affected by the lipid composition of the ER membrane and its collective membrane stiffness. The ER is also a hotspot of lipid biosynthesis including sterols, glycerophospholipids, ceramides and neural storage lipids. The unfolded protein response (UPR) bears an evolutionary conserved, dual sensitivity to both protein-folding imbalances in the ER lumen and aberrant compositions of the ER membrane, referred to as lipid bilayer stress (LBS). Through transcriptional and non-transcriptional mechanisms, the UPR upregulates the protein folding capacity of the ER and balances the production of proteins and lipids to maintain a functional secretory pathway. In this review, we discuss how UPR transducers sense unfolded proteins and LBS with a particular focus on their role as guardians of the secretory pathway.
Highlights
ATF6p50 induces an expansion of the endoplasmic reticulum (ER) membrane [37,38] and upregulates numerous genes encoding for ER chaperones, ER-luminal disulfide oxidoreductases, and ER-associated degradation (ERAD) components [38,51,52,53]
We have proposed that anInositol overcrowding of the ER lipid with membrane proteins of the late secretory pathway, exhibit‐ As an abundant lipid building block, inositol is found in various lipids including phosing a higher average number of hydrophobic transmembrane residues, causes lipid bilayer stress (LBS) and unfolded protein response (UPR) activation [136]
The UPR has a dual sensitivity for both unfolded proteins [24] and aberrant ER membrane stiffening [41,136] to control the biosynthetic rates of lipids, secretory proteins, and membrane proteins
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The UPR (1) lowers the global rate of protein production, (2) upregulates the rate of membrane lipid biosynthesis, (3) induces the production of ER-luminal chaperones and components of the ERAD machinery, and (4) expands the capacity of the secretory pathway [24]. If these adaptive responses are insufficient to restore ER homeostasis, the prolonged activity of the UPR can lead to cell death [24]. Before going into a more detailed discussion of the signals that lead to UPR activation, we will introduce the three branches of the mammalian UPR
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