The Unfolded Protein Response as Guardian of the Secretory Pathway

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 membrane insertion of proteins, 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 metabolism for membrane lipids 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.

A new technology for isolating organellar membranes provides fingerprints of lipid bilayer stress

“…Because transmembrane proteins differ substantially in their shape and hydrophobic thickness depending on their final subcellular destination and function (Sharpe et al, 2010;Quiroga et al, 2013;Lorent et al, 2017Lorent et al, , 2020, a particularly soft and deformable membrane environment can provide a suitable environment for their folding and assembly in macromolecular complexes (Radanović & Ernst, 2021) and may also reduce the barrier for membrane protein integration via molecular invertases (Wu & Rapoport, 2021). In fact, the machineries that insert and remove membrane proteins into and from the ER, respectively, induce a local thinning of the membrane, presumably to lower the energy barrier for insertion and extraction (Wu & Rapoport, 2021).…”

“…Having shown the ability of the ER to adjust its membrane composition, we turned our attention to the stressed ER. Lipid bilayer stress is a collective term for aberrant ER membrane compositions activating the UPR (Ho et al, 2018;Radanović & Ernst, 2021). The acute depletion of inositol causes a robust, but transient UPR without triggering a substantial accumulation of misfolded proteins (Supplementary Figure S3F) (Cox et al, 1997;Promlek et al, 2011;Lajoie et al, 2012).…”

Clinical and biological relevance of CREB3L1 in Philadelphia chromosome-negative myeloproliferative neoplasms

“…CREB3L1 overexpression was observed in platelets and no other PB cell fractions, implying that this gene expression is cell-specific. In the megakaryocytes maturation, endomitotic replication, cytoplasmic remodeling, and extra-membrane production occur, resulting in dynamic changes in the secretory pathway associated with UPR [44,45]. Therefore, we hypothesized that CREB3L1 is induced to make cells resistant to the extra ER stress [46] caused by ectopic activation of JAK2 signaling during megakaryocyte maturation in MPN.…”