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1.
iScience ; 24(10): 103185, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34604721

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has elicited a unique mobilization of the scientific community to develop efficient tools to understand and combat the infection. Like other coronavirae, SARS-CoV-2 hijacks host cell secretory machinery to produce viral proteins that compose the nascent virions; including spike (S), envelope (E), and membrane (M) proteins, the most exposed transmembrane proteins to the host immune system. As antibody response is part of the anti-viral immune arsenal, we investigate the immunogenic potential of S, E, and M using a human cell-based system to mimic membrane insertion and N-glycosylation. Both S and M elicit specific Ig production in patients with SARS-CoV-2. Patients with moderate and severe diseases exhibit elevated Ig responses. Finally, reduced Ig binding was observed with spike G614 compared to D614 variant. Altogether, our assay points toward an unexpected immune response against M and represents a powerful tool to test humoral responses against actively evolving SARS-CoV-2 variants and vaccine effectiveness.

2.
Cancer Res ; 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493594

RESUMO

Therapies targeting the tyrosine kinase receptor HER2 have significantly improved survival of HER2+ cancer patients. However, both de novo and acquired resistance remain a challenge, particularly in the brain metastatic setting. Here we report that, unlike other HER tyrosine kinase receptors, HER2 possesses a binding motif in its cytosolic juxtamembrane region that allows interaction with members of the ezrin/radixin/moesin (ERM) family. Under physiological conditions, this interaction controls the localization of HER2 in ERM-enriched domains and stabilizes HER2 in a catalytically repressed state. In HER2+ breast cancers, low expression of moesin correlated with increased HER2 expression. Restoring expression of ERM proteins in HER2+ breast cancer cells was sufficient to revert HER2 activation and inhibit HER2-dependent proliferation. A high-throughput assay recapitulating the HER2/ERM interaction allowed for screening of about 1500 approved drugs. From this screen, Zuclopenthixol, an anti-psychotic drug that behaved as a moesin-mimicking compound, was found to directly bind the juxtamembrane region of HER2 and specifically inhibit HER2 activation in HER2+ cancers, as well as activation of oncogenic mutated and truncated forms of HER2. Zuclopenthixol efficiently inhibited HER2-positive breast tumor progression in vitro and in vivo and, more importantly, showed significant activity on HER2-positive brain tumor progression. Collectively, these data reveal a novel class of allosteric HER2 inhibitors, increasing the number of approaches to consider for intervention on HER2+ breast cancers and brain metastases.

3.
Biochem J ; 478(15): 2953-2975, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34375386

RESUMO

The Unfolded Protein response is an adaptive pathway triggered upon alteration of endoplasmic reticulum (ER) homeostasis. It is transduced by three major ER stress sensors, among which the Inositol Requiring Enzyme 1 (IRE1) is the most evolutionarily conserved. IRE1 is an ER-resident type I transmembrane protein exhibiting an ER luminal domain that senses the protein folding status and a catalytic kinase and RNase cytosolic domain. In recent years, IRE1 has emerged as a relevant therapeutic target in various diseases including degenerative, inflammatory and metabolic pathologies and cancer. As such several drugs altering IRE1 activity were developed that target either catalytic activity and showed some efficacy in preclinical pathological mouse models. In this review, we describe the different drugs identified to target IRE1 activity as well as their mode of action from a structural perspective, thereby identifying common and different modes of action. Based on this information we discuss on how new IRE1-targeting drugs could be developed that outperform the currently available molecules.

4.
Biochem Pharmacol ; 192: 114737, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34411568

RESUMO

The unfolded protein response (UPR) is an adaptive mechanism that regulates protein and cellular homeostasis. Three endoplasmic reticulum (ER) membrane localized stress sensors, IRE1, PERK and ATF6, coordinate the UPR in order to maintain ER proteostasis and cell survival, or induce cell death when homeostasis cannot be restored. However, recent studies have identified alternative functions for the UPR in developmental biology processes and cell fate decisions under both normal and cancerous conditions. In cancer, increasing evidence points towards the involvement of the three UPR sensors in oncogenic reprogramming and the regulation of tumor cells endowed with stem cell properties, named cancer stem cells (CSCs), that are considered to be the most malignant cells in tumors. Here we review the reported roles and underlying molecular mechanisms of the three UPR sensors in regulating stemness and differentiation, particularly in solid tumor cells, processes that have a major impact on tumor aggressiveness. Mainly PERK and IRE1 branches of the UPR were found to regulate CSCs and tumor development and examples are provided for breast cancer, colon cancer and aggressive brain tumors, glioblastoma. Although the underlying mechanisms and interactions between the different UPR branches in regulating stemness in cancer need to be further elucidated, we propose that PERK and IRE1 targeted therapy could inhibit self-renewal of CSCs or induce differentiation that is predicted to have therapeutic benefit. For this, more specific UPR modulators need to be developed with favorable pharmacological properties that together with patient stratification will allow optimal evaluation in clinical studies.

5.
Traffic ; 22(10): 362-363, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34338403

RESUMO

In this article we discuss implications of the recent discovery of glycoRNAs found to be present at the cell surface of mammalian cells which was reported by Flynn et al. Cell 2021.

6.
J Exp Clin Cancer Res ; 40(1): 271, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34452625

RESUMO

Epithelial ovarian cancer (EOC) is the most common gynecologic disorder. Even with the recent progresses made towards the use of new therapeutics, it still represents the most lethal gynecologic malignancy in women from developed countries.The discovery of the anterior gradient proteins AGR2 and AGR3, which are highly related members belonging to the protein disulfide isomerase (PDI) family, attracted researchers' attention due to their putative involvement in adenocarcinoma development. This review compiles the current knowledge on the role of the AGR family and the expression of its members in EOC and discusses the potential clinical relevance of AGR2 and AGR3 for EOC diagnosis, prognosis, and therapeutics.A better understanding of the role of the AGR family may thus provide new handling avenues for EOC patients.

7.
FEBS J ; 288(16): 4728-4729, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34398531

RESUMO

With the current issue of The FEBS Journal, we are introducing a new category of invited review article contributions on Emerging Methods and Technologies. These articles provide an overview and discussion of recent, emerging methods that significantly advance and improve research efforts in the different fields of molecular and cellular research of our The FEBS Journal authors and readers. Deputy Editorial Manager Manuel Breuer and our Emerging Methods and Technologies Commissioning Editor Eric Chevet introduce the series.


Assuntos
Doenças Autoimunes/imunologia , Proteínas de Membrana/metabolismo , Neoplasias/imunologia , Polietilenotereftalatos/metabolismo , Polissacarídeos/imunologia , Humanos , Proteínas de Membrana/análise , Neoplasias/terapia , Polissacarídeos/química
8.
Prog Mol Subcell Biol ; 59: 197-214, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34050868

RESUMO

The endoplasmic reticulum, as the site of synthesis for proteins in the secretory pathway has evolved select machineries to ensure the correct folding and modification of proteins. However, sometimes these quality control mechanisms fail and proteins are misfolded. Other factors, such as nutrient deprivation, hypoxia or an increased demand on protein synthesis can also cause the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum. There are mechanisms that recognise and deal with this accumulation of protein through degradation and/or export. Many diseases are associated with aberrant quality control mechanisms, and among these, cancer has emerged as a group of diseases that rely on endoplasmic reticulum homeostasis to sustain development and growth. The knowledge of how protein quality control operates in cancer has identified opportunities for these pathways to be pharmacologically targeted, which could lead to newer or more effective treatments in the future.


Assuntos
Retículo Endoplasmático , Neoplasias , Proteostase , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/genética , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Dobramento de Proteína , Proteostase/genética
10.
EMBO Rep ; 22(5): e51412, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33710763

RESUMO

In the past decades, many studies reported the presence of endoplasmic reticulum (ER)-resident proteins in the cytosol. However, the mechanisms by which these proteins relocate and whether they exert cytosolic functions remain unknown. We find that a subset of ER luminal proteins accumulates in the cytosol of glioblastoma cells isolated from mouse and human tumors. In cultured cells, ER protein reflux to the cytosol occurs upon ER proteostasis perturbation. Using the ER luminal protein anterior gradient 2 (AGR2) as a proof of concept, we tested whether the refluxed proteins gain new functions in the cytosol. We find that refluxed, cytosolic AGR2 binds and inhibits the tumor suppressor p53. These data suggest that ER reflux constitutes an ER surveillance mechanism to relieve the ER from its contents upon stress, providing a selective advantage to tumor cells through gain-of-cytosolic functions-a phenomenon we name ER to Cytosol Signaling (ERCYS).


Assuntos
Degradação Associada com o Retículo Endoplasmático , Retículo Endoplasmático , Animais , Citosol/metabolismo , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Camundongos , Proteínas/metabolismo
11.
Biochim Biophys Acta Mol Cell Res ; 1868(6): 119001, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33705817

RESUMO

Endoplasmic Reticulum (ER) stress signaling is an adaptive mechanism triggered when protein folding demand overcomes the folding capacity of this compartment, thereby leading to the accumulation of improperly folded proteins. This stress signaling pathway is named the Unfolded Protein Response (UPR) and aims at restoring ER homeostasis. However, if this fails, mechanisms orienting cells towards death processes are initiated. Herein, we summarize the most recent findings connecting ER stress and the UPR with identified death mechanisms including apoptosis, necrosis, pyroptosis, ferroptosis, and autophagy. We highlight new avenues that could be investigated and controlled through actionable mechanisms in physiology and pathology.


Assuntos
Estresse do Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Resposta a Proteínas não Dobradas , Animais , Apoptose , Autofagia , Ferroptose , Regulação da Expressão Gênica , Humanos
12.
FEBS J ; 288(13): 4081-4097, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33403797

RESUMO

Nuclear protein 1 (NUPR1) is a stress response protein overexpressed upon cell injury in virtually all organs including the exocrine pancreas. Despite NUPR1's well-established role in the response to cell stress, the molecular and structural machineries triggered by NUPR1 activation remain largely debated. In this study, we uncover a new role for NUPR1, participating in the unfolded protein response (UPR) and the integrated stress response. Biochemical results and ultrastructural morphological observations revealed alterations in the UPR of acinar cells of germline-deleted NUPR1 murine models, consistent with the inability to restore general protein synthesis after stress induction. Bioinformatic analysis of NUPR1-interacting partners showed significant enrichment in translation initiation factors, including eukaryotic initiation factor (eIF) 2α. Co-immunoprecipitation and proximity ligation assays confirmed the interaction between NUPR1 and eIF2α and its phosphorylated form (p-eIF2α). Furthermore, our data suggest loss of NUPR1 in cells results in maintained eIF2α phosphorylation and evaluation of nascent proteins by click chemistry revealed that NUPR1-depleted PANC-1 cells displayed a slower poststress protein synthesis recovery when compared to wild-type. Combined, these data propose a novel role for NUPR1 in the integrated stress response pathway, at least partially through promoting efficient PERK branch activity and resolution through a unique interaction with eIF2α.


Assuntos
Proteínas de Ligação a DNA/genética , Estresse do Retículo Endoplasmático/genética , Fator de Iniciação 2 em Eucariotos/genética , Regulação da Expressão Gênica , Proteínas de Neoplasias/genética , Pâncreas/metabolismo , Resposta a Proteínas não Dobradas/genética , Células Acinares/metabolismo , Células Acinares/ultraestrutura , Animais , Western Blotting , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Humanos , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Proteínas de Neoplasias/metabolismo , Pâncreas/citologia , Pâncreas/ultraestrutura , Ligação Proteica , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
FEBS J ; 288(3): 945-960, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32446294

RESUMO

Inositol-requiring enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease that is a major mediator of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Tumour cells experience ER stress due to adverse environmental cues such as hypoxia or nutrient shortage and high metabolic/protein-folding demand. To cope with those stresses, cancer cells utilise IRE1 signalling as an adaptive mechanism. Here, we report the discovery of the FDA-approved compounds methotrexate, cefoperazone, folinic acid and fludarabine phosphate as IRE1 inhibitors. These were identified through a structural exploration of the IRE1 kinase domain using IRE1 peptide fragment docking and further optimisation and pharmacophore development. The inhibitors were verified to have an impact on IRE1 activity in vitro and were tested for their ability to sensitise human cell models of glioblastoma multiforme (GBM) to chemotherapy. We show that all molecules identified sensitise glioblastoma cells to the standard-of-care chemotherapy temozolomide (TMZ).

14.
Biochim Biophys Acta Mol Cell Res ; 1868(3): 118920, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33278424

RESUMO

The human Anterior GRadient 2 (AGR2) protein is an Endoplasmic Reticulum (ER)-resident protein which belongs to the Protein-Disulfide Isomerase (PDI) superfamily and is involved to productive protein folding in the ER. As such AGR2, often found overexpressed in adenocarcinomas, contributes to tumour development by enhancing ER proteostasis. We previously demonstrated that AGR2 is secreted (extracellular AGR2 (eAGR2)) in the tumour microenvironment and plays extracellular roles independent of its ER functions. Herein, we show that eAGR2 triggers cell proliferation and characterize the underlying molecular mechanisms. We demonstrate that eAGR2 enhances tumour cell growth by repressing the tumour suppressor p21CIP1. Our findings shed light on a novel mechanism through which eAGR2 behaves as a growth factor in the tumour microenvironment, independently of its ER function, thus promoting tumour cell growth through repression of p21CIP1. Our results provide a rationale for targeting eAGR2/p21CIP1-based signalling as a potential therapeutic target to impede tumour growth.

15.
EMBO Rep ; 21(12): e51929, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33274581

RESUMO

Endoplasmic reticulum (ER) stress signaling has long been associated with various pathological states in particular with the development of diseases with an underlying inflammation, such as diabetes, liver or cardiovascular dysfunctions, and cancer. ER stress signaling is mediated by three stress sensors. The most evolutionarily conserved one, the inositol-requiring enzyme 1 alpha (IRE1), transduces most of the signals through an endoribonuclease (RNase) activity toward RNAs including mRNAs and microRNAs (miRNAs). By exploring phosphoinositide signaling in human macrophages, Hamid and colleagues discovered a novel function of IRE1 RNase that through the cleavage of pre-miR-2317 generates a mature miR-2317 independently of the canonical Dicer endonuclease to yield specific biological outcomes (Hamid et al, 2020).


Assuntos
MicroRNAs , Estresse do Retículo Endoplasmático/genética , Endorribonucleases/genética , Humanos , Inositol , Macrófagos , MicroRNAs/genética , Fosfatidilinositóis , Proteínas Serina-Treonina Quinases/genética
16.
Trends Cell Biol ; 30(11): 881-891, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33036871

RESUMO

Sustaining both proteome and genome integrity (GI) requires the integration of a wide range of mechanisms and signaling pathways. These comprise, in particular, the unfolded protein response (UPR) and the DNA damage response (DDR). These adaptive mechanisms take place respectively in the endoplasmic reticulum (ER) and in the nucleus. UPR and DDR alterations are associated with aging and with pathologies such as degenerative diseases, metabolic and inflammatory disorders, and cancer. We discuss the emerging signaling crosstalk between UPR stress sensors and the DDR, as well as their involvement in cancer biology.

17.
Cancer Lett ; 494: 73-83, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32882336

RESUMO

Glioblastoma multiforme (GBM) is the most severe primary brain cancer. Despite an aggressive treatment comprising surgical resection and radio/chemotherapy, patient's survival post diagnosis remains short. A limitation for success in finding novel improved therapeutic options for such dismal disease partly lies in the lack of a relevant animal model that accurately recapitulates patient disease and standard of care. In the present study, we have developed an immunocompetent GBM model that includes tumor surgery and a radio/chemotherapy regimen resembling the Stupp protocol and we have used this model to test the impact of the pharmacological inhibition of the endoplasmic reticulum (ER) stress sensor IRE1, on treatment efficacy.


Assuntos
Benzopiranos/administração & dosagem , Neoplasias Encefálicas/terapia , Terapia Combinada/métodos , Glioblastoma/terapia , Morfolinas/administração & dosagem , Animais , Benzopiranos/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Linhagem Celular Tumoral , Craniotomia , Tratamento Farmacológico , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/imunologia , Humanos , Imunocompetência , Injeções Intralesionais , Camundongos , Morfolinas/farmacologia , Terapia Neoadjuvante , Radioterapia , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Cancers (Basel) ; 12(8)2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32784704

RESUMO

Sigma receptor 1 (SigR1) is an endoplasmic reticulum resident integral membrane protein whose functions remain unclear. Although the liver shows the highest expression of SigR1, its role in this organ is unknown. SigR1 is overexpressed in many cancers and its expression is correlated to hormonal status in hormone-dependent cancers. To better understand the role of SigR1 in hepatocytes we focused our work on the regulation of its expression in tumoral liver. In this context, hepatocellular adenomas, benign hepatic tumors associated with estrogen intake are of particular interest. The expression of SigR1 mRNA was assessed in hepatocellular adenoma (HCA) patients using qPCR. The impact of estrogen on the expression of SigR1 was studied in vivo (mice) and in vitro (HepG2 and Huh7 cells). The effect of HNF1α on the expression of SigR1 was studied in vivo by comparing wild type mice to HNF1 knockout mice. Estrogen enhanced SigR1 expression through its nuclear receptor ERα. HNF1α mutated HCA (H-HCA) significantly overexpressed SigR1 compared to all other HCA subtypes. HNF1 knockout mice showed an increase in SigR1 expression. Overexpressing SigR1 in cellular models increases proliferation rate and storage of lipid droplets, which phenocopies the H-HCA phenotype. SigR1 is involved in hepatocyte proliferation and steatosis and may play an important role in the control of the H-HCA phenotype.

19.
Trends Cancer ; 6(12): 1018-1030, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32861679

RESUMO

IRE1α (inositol requiring enzyme 1 alpha) is one of the main transducers of the unfolded protein response (UPR). IRE1α plays instrumental protumoral roles in several cancers, and high IRE1α activity has been associated with poorer prognoses. In this context, IRE1α has been identified as a potentially relevant therapeutic target. Pharmacological inhibition of IRE1α activity can be achieved by targeting either the kinase domain or the RNase domain. Herein, the recent advances in IRE1α pharmacological targeting is summarized. We describe the identification and optimization of IRE1α inhibitors as well as their mode of action and limitations as anticancer drugs. The potential pitfalls and challenges that could be faced in the clinic, and the opportunities that IRE1α modulating strategies may present are discussed.

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