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| Open AccessPan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway
Imidazolopiperazines (IZPs) are a class of compounds under clinical development for malaria, but their mechanism of action is unclear. Here, the authors show that IZPs inhibit the parasite’s secretory pathway, affecting protein trafficking and export.
- Gregory M. LaMonte
- , Frances Rocamora
- & Elizabeth A. Winzeler
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Article
| Open AccessPharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy
Inhibition of PERK, an endoplasmic reticulum (ER) unfolded protein response (UPR) protein, is a potential pharmacological target for cancer treatment. Here, the authors show that inhibition of PERK under ER stress affects trafficking from the ER to the surface of several key receptor tyrosine kinases, suggesting a selective ER retention.
- Mohamed Mahameed
- , Shatha Boukeileh
- & Boaz Tirosh
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Article
| Open AccessSelective EMC subunits act as molecular tethers of intracellular organelles exploited during viral entry
The endoplasmic reticulum membrane protein complex (EMC) is known to play a role in SV40 viral infection but precise mechanisms are unclear. Here, the authors report that the EMC acts as tether of late endosome–endoplasmic reticulum interorganellar membrane contact sites to promote SV40 viral infection.
- Parikshit Bagchi
- , Mauricio Torres
- & Billy Tsai
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Article
| Open AccessRegulation of lipid saturation without sensing membrane fluidity
Cells maintain membrane fluidity by regulating lipid saturation, but the molecular mechanisms of this homeoviscous adaptation remain poorly understood. Here authors reconstituted the core machinery for regulating lipid saturation in baker’s yeast to directly characterize its response to defined membrane environments and uncover its mode-of-action.
- Stephanie Ballweg
- , Erdinc Sezgin
- & Robert Ernst
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Article
| Open AccessMelanoblast transcriptome analysis reveals pathways promoting melanoma metastasis
Metastatic cells can mimic many of the phenotypic behaviors of embryonic cells. Here, the authors generate a melanoblast-specific transcriptome using a genetically engineered mouse model and identify KDELR3 as a pro-metastasis gene in melanoma.
- Kerrie L. Marie
- , Antonella Sassano
- & Pravin J. Mishra
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| Open AccessDynamic constriction and fission of endoplasmic reticulum membranes by reticulon
The endoplasmic reticulum (ER) is an intracellular network characterized by highly dynamic behavior whose control mechanisms are unclear. Here, the authors show that the ER-membrane protein Reticulon (Rtnl1) can constrict ER bilayers and lead to ER fission.
- Javier Espadas
- , Diana Pendin
- & Andrea Daga
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Article
| Open AccessQuantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process
How epigenetics coordinate with genetics to impact protein fitness is unknown. Here, using a Variation Spatial Profiling strategy and machine learning, the authors map HDAC impact on a full set of Niemann pick C1 disease variants to quantitate an unanticipated plasticity in central dogma.
- Chao Wang
- , Samantha M. Scott
- & William E. Balch
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Article
| Open AccessESCRT-III-driven piecemeal micro-ER-phagy remodels the ER during recovery from ER stress
The ER increases in size upon stress in response to the UPR and is remodelled after the stressor is removed by a process called recov-ER-phagy. Here, the authors show remodelling to pre-stress ER size occurs by micro-ER-phagy requiring ESCRT-III components CHMP4B and VPS4A.
- Marisa Loi
- , Andrea Raimondi
- & Maurizio Molinari
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Article
| Open AccessConstitutive XBP-1s-mediated activation of the endoplasmic reticulum unfolded protein response protects against pathological tau
Accumulation of abnormal tau protein drives neurodegeneration in Alzheimer’s disease and related dementia disorders. Here, the authors demonstrate the endoplasmic reticulum unfolded protein response mediator XBP-1 controls pathological tau accumulation and the resultant neurodegeneration in a transgenic C. elegans model.
- Sarah M. Waldherr
- , Timothy J. Strovas
- & Brian C. Kraemer
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Article
| Open AccessGut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5−/− mice
RNF5 is a ubiquitin ligase regulating ER stress response. Here the authors show that Rnf5 deficiency potentiates immune response against melanoma via altered microbiota, and isolate bacterial strains that confer the same phenotype to wild type mice.
- Yan Li
- , Roberto Tinoco
- & Ze’ev A. Ronai
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Article
| Open AccessQuantitative analysis of plant ER architecture and dynamics
Quantitative study of endoplasmic reticulum (ER) structure and dynamics has been a challenge. Here, the authors introduce software to automatically extract ER network elements from multi-dimensional fluorescence images of plant ER and to quantify structure, topology, protein localization and dynamics.
- Charlotte Pain
- , Verena Kriechbaumer
- & Mark Fricker
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Article
| Open AccessMANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP
The role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in maintenance of protein folding homeostasis inside the ER has remained unclear. Here the authors determine the structure of the complex between MANF and the ER-localized chaperone BiP and provide evidence that MANF serves as an anti-nucleotide exchange factor for BiP.
- Yahui Yan
- , Claudia Rato
- & David Ron
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Article
| Open AccessNuclear lipid droplets derive from a lipoprotein precursor and regulate phosphatidylcholine synthesis
The origin and physiological significance of lipid droplets (LDs) in the nucleus is not clear. Here authors show that nucleoplasmic LDs in hepatocytes are derived from apolipoprotein B (ApoB)-free lumenal LDs and constitute a feedback mechanism to regulate PC synthesis in accordance with ER stress.
- Kamil Sołtysik
- , Yuki Ohsaki
- & Toyoshi Fujimoto
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Article
| Open AccessPharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis
Imbalanced proteostasis is associated with diverse diseases, including ischemia/reperfusion injury in the heart. Here the authors show that the ATF6 arm of the unfolded protein response can be pharmacologically activated with a small molecule in vivo, providing protection from ischemia/reperfusion injury in the heart, the brain, and the kidney.
- Erik A. Blackwood
- , Khalid Azizi
- & Christopher C. Glembotski
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Article
| Open AccessTransmembrane but not soluble helices fold inside the ribosome tunnel
Integral membrane proteins are assembled into the ER membrane via the ribosome-translocon channel. Here authors use in vitro translation assays and MD simulations to show that folding in the ribosome is favorable for TM helices, but unfavorable for soluble helices.
- Manuel Bañó-Polo
- , Carlos Baeza-Delgado
- & Ismael Mingarro
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Article
| Open AccessProteomics reveals signal peptide features determining the client specificity in human TRAP-dependent ER protein import
While Sec61 enables ER import of all polypeptides with N-terminal signal peptides, only selected clients are accepted for TRAP-assisted ER import. Here, the authors use a proteomics approach to characterize TRAP-dependent clients, identifying signal peptide features that govern recognition by TRAP.
- Duy Nguyen
- , Regine Stutz
- & Richard Zimmermann
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Article
| Open AccessLipid droplet and peroxisome biogenesis occur at the same ER subdomains
Lipid droplets (LDs) and peroxisomes are both generated by budding off the endoplasmic reticulum (ER). Here, the authors show that the yeast protein Pex30 marks ER subdomains where both LD and peroxisome biogenesis occurs, and identify MCTP2 as the putative mammalian Pex30 ortholog.
- Amit S. Joshi
- , Benjamin Nebenfuehr
- & William A. Prinz
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| Open AccessSeipin and the membrane-shaping protein Pex30 cooperate in organelle budding from the endoplasmic reticulum
Lipid droplets (LDs) and peroxisomes both emerge from the endoplasmic reticulum (ER). Here, the authors show that yeast Seipin and Pex30 proteins act together to regulate budding of these organelles from the same subdomain of the ER.
- Sihui Wang
- , Fatima-Zahra Idrissi
- & Pedro Carvalho
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| Open AccessPhosphorylation of LAMP2A by p38 MAPK couples ER stress to chaperone-mediated autophagy
The endoplasmic reticulum (ER) and lysosome are central to cellular stress responses, but it is unclear how ER stress is signaled to lysosomes. Here the authors show that ER stress activates chaperone-mediated autophagy (CMA) via direct phosphorylation of the CMA receptor LAMP2A by the lysosomal p38 MAPK.
- Wenming Li
- , Jinqiu Zhu
- & Zixu Mao
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| Open AccessER-associated degradation regulates Alzheimer’s amyloid pathology and memory function by modulating γ-secretase activity
Endoplasmic-reticulum associated degradation (ERAD) regulates protein homeostasis. Here the authors identify an ERAD component membralin, and show that it interacts with a member of the γ-secretase complex to regulate β-amyloid (Aβ) pathology and memory deficits in an Alzheimer’s disease model.
- Bing Zhu
- , LuLin Jiang
- & Huaxi Xu
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Article
| Open AccessInfluenza virus genome reaches the plasma membrane via a modified endoplasmic reticulum and Rab11-dependent vesicles
Transport of neo-synthesized influenza A virus viral ribonucleoproteins (vRNPs) from the nucleus to the plasma membrane involves Rab 11 but the mechanism is unclear. Here the authors show that vRNPs are transported through a modified Rab11-positive endoplasmic reticulum and Rab11-dependent vesicles.
- Isabel Fernández de Castro Martin
- , Guillaume Fournier
- & Nadia Naffakh
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| Open AccessBik reduces hyperplastic cells by increasing Bak and activating DAPk1 to juxtapose ER and mitochondria
Bcl-2 interacting killer (Bik) decreases airway epithelial hyperplasia via apoptosis mediated by calcium release from the endoplasmic reticulum (ER), but the mechanism is unclear. Here the authors show that Bik promotes Bak enrichment at the ER to tether mitochondria for efficient calcium transfer.
- Yohannes A. Mebratu
- , Ivan Leyva-Baca
- & Yohannes Tesfaigzi
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Article
| Open AccessORP5 and ORP8 bind phosphatidylinositol-4, 5-biphosphate (PtdIns(4,5)P 2) and regulate its level at the plasma membrane
ORP5/8 are endoplasmic reticulum (ER) membrane proteins implicated in lipid trafficking that localize to ER-plasma membrane (PM) contacts and maintain membrane homeostasis. Here the authors show that PtdIns(4,5)P 2 plays a critical role in the targeting and function of ORP5/8 at the PM.
- Rajesh Ghai
- , Ximing Du
- & Hongyuan Yang
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Article
| Open AccessFortilin binds IRE1α and prevents ER stress from signaling apoptotic cell death
IRE1α is an ER stress sensor, whose activity induces apoptosis. Here, the authors report that fortilin, a pro-survival factor, with yet unknown roles in ER stress, interacts with active IRE1α, inhibits both its kinase end RNase activities, and protects cells from apoptosis both in vitro and in vivo.
- Decha Pinkaew
- , Abhijnan Chattopadhyay
- & Ken Fujise
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Article
| Open AccessDissecting the molecular organization of the translocon-associated protein complex
The translocon-associated protein complex (TRAP) is a crucial component of the endoplasmic reticulum protein translocon. Here the authors study native translocon structures from human disease patients and algae cells to determine the molecular organization of the TRAP complex.
- Stefan Pfeffer
- , Johanna Dudek
- & Friedrich Förster
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Article
| Open AccessAnks1a regulates COPII-mediated anterograde transport of receptor tyrosine kinases critical for tumorigenesis
EphA2/ErbB2 complex is important in promoting breast cancer but the mechanism by which these receptor tyrosine kinases are exported from the endoplasmic reticulum is unknown. Here the authors show that Anks1a acts as a cargo adaptor in sorting EphA2 into COPII vesicles, thus modulating the surface level of EphA2.
- Haeryung Lee
- , Hyuna Noh
- & Soochul Park
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Article
| Open AccessGPRC5A suppresses protein synthesis at the endoplasmic reticulum to prevent radiation-induced lung tumorigenesis
GPRC5A is a retinoic acid inducible gene that is preferentially expressed in lung tissue. Here the authors report that GPRC5A suppresses the translation of EGFR by interfering with the eIF4F complex assembly, thereby limiting lung tumorigenesis, particularly radiation-induced lung tumorigenesis.
- Jian Wang
- , Alton B. Farris
- & Ya Wang
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Article
| Open AccessVCP and ATL1 regulate endoplasmic reticulum and protein synthesis for dendritic spine formation
Protein homeostasis is crucial for maintaining a variety of cellular functions. Here the authors show that valosin-containing protein and its cofactors regulate tubular ER formation and protein synthesis efficiency, thereby control dendritic spine formation in neurons.
- Yu-Tzu Shih
- & Yi-Ping Hsueh
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Article
| Open AccessStructure of the native Sec61 protein-conducting channel
The protein-conducting channel Sec61 is responsible for protein transport and membrane insertion at the endoplasmic reticulum. Here, the authors determine the structure of ribosome-bound Sec61 in a native context, in which it adopts a laterally open conformation, irrespective of its functional state.
- Stefan Pfeffer
- , Laura Burbaum
- & Friedrich Förster
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Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis
The Hippo pathway is a major regulator of organ size and growth control. Here Wu et al. provide evidence for a novel link between the Hippo signalling pathway and the unfolded protein response (UPR) in regulating organ growth and tumorigenesis.
- Hongtan Wu
- , Luyao Wei
- & Dawang Zhou
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Receptor-interacting protein 140 attenuates endoplasmic reticulum stress in neurons and protects against cell death
Uncontrolled calcium release from the endoplasmic reticulum results in cell death and toxicity. Here, the authors show that in neurons, stress induces the export of receptor-interacting protein 140 from the nucleus to the cytosol where it interacts with IP3Receptor, preventing its opening and the detrimental effects of calcium release.
- Xudong Feng
- , Kelly A. Krogh
- & Li-Na Wei
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ATG5 defines a phagophore domain connected to the endoplasmic reticulum during autophagosome formation in plants
Compared with yeast and animal cells, the detailed dynamics of autophagosome extension in plants remain particularly unclear. Here the authors show that the autophagy-related protein, ATG5, forms a torus-shaped domain on the early phagophore in Arabidopsis, and involve the ER in a model for plant autophagosome formation.
- Romain Le Bars
- , Jessica Marion
- & Michele Wolfe Bianchi
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| Open AccessER–mitochondria associations are regulated by the VAPB–PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43
Mutations in the protein TDP-43 are implicated in amyotrophic lateral sclerosis. Here, the authors show that mutant TDP-43 perturbs endoplasmic reticulum (ER)–mitochondria associations by altering interactions between the mitochondrial protein PTPIP51 and the ER protein VAPB.
- Radu Stoica
- , Kurt J. De Vos
- & Christopher C. J. Miller
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| Open AccessConformational targeting of intracellular Aβ oligomers demonstrates their pathological oligomerization inside the endoplasmic reticulum
Intracellular Aß oligomers have been linked to Alzheimer’s disease but details about their biosynthesis and function have been hard to obtain due to the lack of selective approaches for targeting them. Here, Meli et al.develop a strategy using recombinant antibodies to target Aß oligomers in the endoplasmic reticulum of cells, and perform mechanistic studies in cellular models of the disease.
- Giovanni Meli
- , Agnese Lecci
- & Antonino Cattaneo
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TorsinA participates in endoplasmic reticulum-associated degradation
The torsinA protein localizes to the endoplasmic reticulum and, when mutated, causes early onset torsion dystonia. The authors reveal a new role for torsinA in proteosome-mediated degradation of misfolded proteins, and relate this to endoplasmic reticulum stress, in aCaenorhabditis elegansmodel and patient fibroblasts.
- Flávia C. Nery
- , Ioanna A. Armata
- & Xandra O. Breakefield