REVIEW | doi:10.20944/preprints201909.0098.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: unfolded protein response; endoplasmic reticulum; PERK; IRE-1; ATF4
Online: 9 September 2019 (11:54:25 CEST)
The endoplasmic reticulum (ER) comprises a network of tubules and vesicles that constitutes the largest organelle of the eukaryotic cell. Being the location where most proteins are synthesized and folded, it is crucial for the upkeep of cellular homeostasis. In addition, it is the largest ionic calcium reservoir in cells, tightly regulating the levels of this second messenger according to cellular necessities. Disturbed ER homeostasis triggers the activation of an intricate and conserved molecular machinery, termed the unfolded protein response (UPR). Given the impact of this signaling network upon an extensive list of cellular processes, ER stress is involved in the onset and progression of multiple diseases, including cancer and neurodegenerative disorders. There is, for this reason, an increasing number of publications focused on characterizing and/or modulating ER stress, which have resulted in a wide array of techniques employed to study ER-related molecular events. This review aims to sum up the tools available design a study of this nature.
REVIEW | doi:10.20944/preprints202110.0447.v1
Subject: Life Sciences, Biochemistry Keywords: UPR; IRE1; PERK; ATF6; lipid bilayer stress; ER stress; secretory pathway; hydrophobic mismatch; membrane thickness; membrane stiffness
Online: 29 October 2021 (07:57:29 CEST)
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.
REVIEW | doi:10.20944/preprints201912.0040.v1
Subject: Life Sciences, Virology Keywords: unfolded protein response (UPR); integrated stress response (ISR); ATF6; IRE1; XBP1; PERK; ATF4; GADD34; herpesvirus; Kaposi’s sarcoma-associated herpesvirus (KSHV); cytomegalovirus (CMV); herpes simplex virus (HSV)
Online: 4 December 2019 (04:38:02 CET)
Herpesviruses usurp cellular stress responses to avoid immune detection while simultaneously promoting viral replication and spread. The unfolded protein response (UPR) is an evolutionarily conserved stress response that is activated when the protein load in the ER saturates its chaperone folding capacity causing an accrual of misfolded proteins. Through translational and transcriptional reprogramming, the UPR aims to restore protein homeostasis; however, if this fails the cell undergoes apoptosis. It is commonly thought that many enveloped viruses, including herpesviruses, may activate the UPR due to saturation of the ER with nascent glycoproteins and thus these viruses may have evolved mechanisms to evade the potentially negative effects of UPR signaling. Over the past fifteen years there has been considerable effort to provide evidence that different viruses may reprogram the UPR to promote viral replication. Here we provide an overview of the molecular events of UPR activation, signaling and transcriptional outputs, and highlight key findings that demonstrate that the UPR is an important cellular stress response that herpesviruses have hijacked to facilitate persistent infection.