bims-unfpre 2020-11-08 papers

Issue of 2020–11–08
seven papers selected by
Susan Logue, University of Manitoba

EMBO Rep. 2020 Nov 02. e51462

Inositol-requiring enzyme-1 regulates phosphoinositide signaling lipids and macrophage growth.

Syed Muhammad Hamid, Mevlut Citir, Erdem Murat Terzi, Ismail Cimen, Zehra Yildirim, Asli Ekin Dogan, Begum Kocaturk, Umut Inci Onat, Moshe Arditi, Christian Weber, Alexis Traynor-Kaplan, Carsten Schultz, Ebru Erbay.

The ER-bound kinase/endoribonuclease (RNase), inositol-requiring enzyme-1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1's one known, specific RNA target, X box-binding protein-1 (XBP1) or the RNA substrates of IRE1-dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 plays an unprecedented role in regulating phosphatidylinositide-derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross-talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1's RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P3 ) 5-phosphatase-2 (INPPL1) is a direct target of miR-2137, which controls PI(3,4,5)P3 levels in macrophages. The modulation of cellular PI(3,4,5)P3 /PIP2 ratio and anabolic mTOR signaling by the IRE1-induced miR-2137 demonstrates how the ER can provide a critical input into cell growth decisions.

Keywords: ER stress; hyperlipidemia; mTOR signaling; macrophage; microRNA

DOI: https://doi.org/10.15252/embr.202051462

J Biol Chem. 2020 Nov 03. pii: jbc.RA120.015271. [Epub ahead of print]

Misfolding, altered membrane distributions, and the unfolded protein response contribute to pathogenicity differences in Na,K-ATPase ATP1A3 mutations.

Elena Arystarkhova, Laurie J Ozelius, Allison Brashear, Kathleen J Sweadner.

Missense mutations in ATP1A3, the α3 isoform of Na,K-ATPase, cause neurological phenotypes that differ greatly in symptoms and severity. A mechanistic basis for differences is lacking, but reduction of activity alone cannot explain them. Isogenic cell lines with endogenous α1 and inducible exogenous α3 were constructed to compare mutation properties. Na,K-ATPase is made in endoplasmic reticulum, but glycan-free catalytic α subunit complexes with glycosylated β subunit in the ER to proceed through Golgi and post-Golgi trafficking. We previously observed classic evidence of protein misfolding in mutations with severe phenotypes: differences in ER retention of endogenous β1 subunit, impaired trafficking of α3, and cytopathology, suggesting that they misfold during biosynthesis. Here we tested two mutations associated with different phenotypes: D923N, which has a median age of onset of hypotonia or dystonia at 3 years, and L924P, with severe infantile epilepsy and profound impairment. Misfolding during biosynthesis in the ER activates the unfolded protein response (UPR), a multi-armed program that enhances protein folding capacity, and if that fails, triggers apoptosis. L924P showed more nascent protein retention in ER than D923N; more ER-associated degradation of α3 (ERAD); larger differences in Na,K-ATPase subunit distributions among subcellular fractions; and greater inactivation of eIF2α, a major defensive step of the UPR. In L924P there was also altered subcellular distribution of endogenous α1 subunit, analogous to a dominant negative effect. Both mutations showed pro-apoptotic sensitization by reduced phosphorylation of BAD. Encouragingly, however, 4-phenylbutyrate (4PBA), a pharmacological corrector, reduced L924P ER retention, increased α3 expression, and restored morphology.

Keywords: 4-phenylbutyrate, 4PBA; N-linked glycosylation; Na+/K+-ATPase; endocytosis; endoplasmic reticulum stress (ER stress); endoplasmic-reticulum-associated protein degradation (ERAD); eukaryotic initiation factor 2 (eIF2); genetic disease; protein misfolding; subcellular fractionation; unfolded protein response (UPR)

DOI: https://doi.org/10.1074/jbc.RA120.015271

Biochem Biophys Rep. 2020 Dec;24 100829

A pilot study on gene expression of endoplasmic reticulum unfolded protein response in chronic kidney disease.

Rasha G Mostafa, Abd El-Aleem Hassan Abd El-Aleem, Eman Abdella Mahmoud Fouda, Fardous Rabea Ahmed Taha, Khaled Mohamed Amin Elzorkany.

Background: Chronic kidney disease (CKD) is a worldwide public health problem due to its increasing prevalence worldwide. Endoplasmic reticulum (ER) stress has been shown to play a role in the pathogenesis of various renal diseases in humans. It leads to the activation of the unfolded protein response (UPR) which triggers three known trans membrane sensors in the ER: activating transcription factor 6 (ATF6), inositol-requiring enzyme I (IRE1), and PKR (double-stranded RNA-dependent protein kinase)-like ER protein kinase (PERK). The activation of these signal transduction pathways can result in cell death, inflammation, and fibrosis in the context of CKD.
Objectives: The aim of this study was to detect the level of gene expression of activating transcription factor 6 (ATF6), inositol-requiring enzyme I (IRE1), and PKR (double-stranded RNA-dependent protein kinase)-like ER protein kinase (PERK) in chronic kidney disease patients.
Subjects and methods: This study was carried out on eighty subjects, 50 patients with CKD (25 with hypertension and 25 without hypertension) and 30 healthy subjects served as controls. All studied subjects underwent laboratory investigations, including CBC, Serum Lipid profile: Total cholesterol, Triglycerides, HDL-cholesterol and LDL-cholesterol, liver and kidney functions, fasting and 2 h postprandial blood glucose and HbA1C, serum level of IL6 and gene expression of ATF6, IRE1 and PERK using real time PCR technique.
Results: There was a significant increase in relative quantitation (RQ) of gene expression of IRE1, ATF6 and PERK in chronic kidney patient groups with hypertension and without hypertension compared to control group. Also, there was a significant positive correlation of PERK and ATF6 gene expressions and a significant negative correlation of PERK gene expressions and GFR in groups I&II.
Conclusion: Endoplasmic reticulum (ER) stress occurs in CKD with activation of gene expression of three trans-membrane sensors in the ER: activating transcription factor 6 (ATF6), inositol-requiring enzyme I (IRE1), and PKR (double-stranded RNA-dependent protein kinase)-like ER protein kinase (PERK).

Keywords: CDK; ER stress; IRE1 and ATF6 gene expressions; PERK

DOI: https://doi.org/10.1016/j.bbrep.2020.100829

PLoS Genet. 2020 Nov 02. 16(11): e1009172

Suppression of retinal degeneration by two novel ERAD ubiquitin E3 ligases SORDD1/2 in Drosophila.

Jaiwei Xu, Haifang Zhao, Tao Wang.

Mutations in the gene rhodopsin are one of the major causes of autosomal dominant retinitis pigmentosa (adRP). Mutant forms of Rhodopsin frequently accumulate in the endoplasmic reticulum (ER), cause ER stress, and trigger photoreceptor cell degeneration. Here, we performed a genome-wide screen to identify suppressors of retinal degeneration in a Drosophila model of adRP, carrying a point mutation in the major rhodopsin, Rh1 (Rh1G69D). We identified two novel E3 ubiquitin ligases SORDD1 and SORDD2 that effectively suppressed Rh1G69D-induced photoreceptor dysfunction and retinal degeneration. SORDD1/2 promoted the ubiquitination and degradation of Rh1G69D through VCP (valosin containing protein) and independent of processes reliant on the HRD1 (HMG-CoA reductase degradation protein 1)/HRD3 complex. We further demonstrate that SORDD1/2 and HRD1 function in parallel and in a redundant fashion to maintain rhodopsin homeostasis and integrity of photoreceptor cells. These findings identify a new ER-associated protein degradation (ERAD) pathway and suggest that facilitating SORDD1/2 function may be a therapeutic strategy to treat adRP.

DOI: https://doi.org/10.1371/journal.pgen.1009172

J Control Release. 2020 Oct 28. pii: S0168-3659(20)30636-2. [Epub ahead of print]

Cell surface GRP78: An emerging imaging marker and therapeutic target for cancer.

Masoud Farshbaf, Ahmad Yari Khosrowshahi, Solmaz Mojarad-Jabali, Amir Zarebkohan, Hadi Valizadeh, Paul R Walker.

As one of the deadliest diseases, cancer frequently resists existing therapeutics because they do not target all cells within a progressing tumor, for example both tumor stem and proliferating cells. This frequently results in enrichment of invasive and metastatic drug-resistant tumor cells subpopulations, cancer recurrence and eventually, patient mortality. Thus, there is an urgent need to identify specific markers, by which the targeted imaging and/or therapeutic "guided missile"-like agents can specifically detect and/or eradicate all cancer cells within a heterogeneous tumor, while leaving the normal cells intact. As a member of heat shock protein 70 (HSP70) superfamily, glucose regulated protein 78 (GRP78) has been documented as a molecular chaperone in the endoplasmic reticulum (ER) which mainly responds to ER stresses in normal cells. There is over-expression of GRP78 on the surface of cancer cells and angiogenic endothelial cells, which makes it a promising target for different types of peptides and antibodies that can be employed for targeted cancer therapy or imaging. In this review, we discuss the biological processes, functional importance and translocation mechanisms of cell surface GRP78 (csGRP78) in tumor cells. As a cancer biomarker, we also review the potential applications of csGRP78 targeted therapy and imaging and finally we suggest a brief roadmap ahead of csGRP78 targeting for targeted theranostic implications.

Keywords: Active targeting; Cancer; GRP78; Imaging; Nanomedicine; Therapy

DOI: https://doi.org/10.1016/j.jconrel.2020.10.055

Apoptosis. 2020 Nov 07.

The interplay between apoptosis and ferroptosis mediated by ER stress.

Go J Yoshida.

Keywords: Apoptosis; ER stress; Erastin; Ferroptosis; Mitochondria

DOI: https://doi.org/10.1007/s10495-020-01641-1

Front Cell Neurosci. 2020 ;14 554548

The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders.

Vignesh Srinivasan, Laura Korhonen, Dan Lindholm.

Neurons are polarized in structure with a cytoplasmic compartment extending into dendrites and a long axon that terminates at the synapse. The high level of compartmentalization imposes specific challenges for protein quality control in neurons making them vulnerable to disturbances that may lead to neurological dysfunctions including neuropsychiatric diseases. Synapse and dendrites undergo structural modulations regulated by neuronal activity involve key proteins requiring strict control of their turnover rates and degradation pathways. Recent advances in the study of the unfolded protein response (UPR) and autophagy processes have brought novel insights into the specific roles of these processes in neuronal physiology and synaptic signaling. In this review, we highlight recent data and concepts about UPR and autophagy in neuropsychiatric disorders and synaptic plasticity including a brief outline of possible therapeutic approaches to influence UPR and autophagy signaling in these diseases.

Keywords: UPR; autophagy; drug; neuropsychiatric disease; synapse

DOI: https://doi.org/10.3389/fncel.2020.554548