ER stress signaling at the interphase between MASH and hepatocellular carcinoma

International audienceHepato-cellular carcinoma (HCC) is the most frequent primary liver cancer with an extremely poor prognosis and often develops on preset of chronic liver diseases. Major risk factors for HCC include metabolic dysfunction-associated steatohepatitis (MASH), a complex multifactorial condition associated with abnormal endoplasmic reticulum (ER) proteostasis. To cope with ER stress, the unfolded protein response (UPR) engages adaptive reactions to restore the secretory capacity of the cell. Recent advances revealed that ER stress signaling plays a critical role in HCC progression. Here we propose that chronic ER stress is a common transversal factor contributing to the transition from liver disease (risk factor) to HCC. Interventional strategies to target the UPR in HCC as cancer therapy are also discussed

Endoplasmic Reticulum stress signaling and the pathogenesis of Non-Alcoholic Fatty Liver Disease

International audienceThe global epidemic of obesity has been accompanied by a rising burden of non-alcoholic fatty liver disease (NAFLD), with manifestations ranging from simple steatosis to non-alcoholic steatohepatitis, potentially developing into hepatocellular carcinoma. Although much attention has focused on NAFLD, its pathogenesis remains largely obscure. The hallmark of NAFLD is the hepatic accumulation of lipids, which subsequently leads to cellular stress and hepatic injury, eventually resulting in chronic liver disease. Abnormal lipid accumulation often coincides with insulin resistance in steatotic livers and is associated with perturbed endoplasmic reticulum (ER) proteostasis in hepatocytes. In response to chronic ER stress, an adaptive signalling pathway known as the unfolded protein response is triggered to restore ER proteostasis. However, the unfolded protein response can cause inflammation, inflammasome activation and, in the case of non-resolvable ER stress, the death of hepatocytes. Experimental data suggest that the unfolded protein response influences hepatic tumour development, aggressiveness and response to treatment, offering novel therapeutic avenues. Herein, we provide an overview of the evidence linking ER stress to NAFLD and discuss possible points of intervention

Autophagy in hepatic adaptation to stress

Autophagy is an evolutionarily ancient process whereby eukaryotic cells eliminate disposable or potentially dangerous cytoplasmic material, to support bioenergetic metabolism and adapt to stress. Accumulating evidence indicates that autophagy operates as a critical quality control mechanism for the maintenance of hepatic homeostasis in both parenchymal (hepatocytes) and non-parenchymal (stellate cells, sinusoidal endothelial cells, Kupffer cells) compartments. In line with this notion, insufficient autophagy has been aetiologically involved in the pathogenesis of multiple liver disorders, including alpha-1-antitrypsin deficiency, Wilson disease, non-alcoholic steatohepatitis, liver fibrosis and hepatocellular carcinoma. Here, we critically discuss the importance of functional autophagy for hepatic physiology, as well as the mechanisms whereby defects in autophagy cause liver disease.Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT), CONICYT FONDECYT: 3180427, 1140549, 1180186. Breakthrough Level 2 grant from the US DoD, Breast Cancer Research Program (BCRP): BC180476P1. Dept. of Radiation Oncology at Weill Cornell Medicine (New York, US). Lytix (Oslo, Norway). Phosplatin (New York, US). Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT), CONICYT FONDAP: 15150012. Takeda Pharmaceutical Company Ltd. P09-015-F. European Commission RD MSCA-RISE: 734749. Michael J Fox Foundation for Parkinson's Research - Target Validation grant: 9277. FONDEF: ID16I10223, D11E1007. Office of Naval Research: N62909-16-1-2003. United States Department of Defense, Air Force Office of Scientific Research (AFOSR): FA9550-16-1-0384. ALSRP Therapeutic Idea Award: AL150111. Muscular Dystrophy Association: 382453. CONICYT Brazil: 441921/2016-7. Ligue contre le Cancer (equipe labellisee). French National Research Agency (ANR). French National Research Agency (ANR). Fondation ARC pour la Recherche sur le Cancer. Region Ile-de-France. Chancelerie des universites de Paris (Legs Poix), Fondation pour la Recherche Medicale (FRM) European Research Area Network on Cardiovascular Diseases (ERACVD, MINOTAUR) Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome Fondation Carrefour Institut National du Cancer (INCA) France: GDW20171100085, GDW20181100051. Inserm (HTE). Inserm Transfert, Institut Universitaire de France. Leducq Foundation. LabEx Immuno-Oncology. RHU Torino Lumiere. Seerave Foundation. SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE). SIRIC Cancer Research and Personalized Medicine (CARPEM)

Serpina1 hepatocyte-specific promoter polymorphism associate with chronic obstructive pulmonary disease in a study of kashmiri ancestry individuals

Different mutations in coding and non-coding sequences of the SERPINA1 gene have been implicated in the pathogenesis of COPD. However, - 10T/C mutation in the hepatocyte-directed promoter region has not been associated with COPD pathogenesis so far. Here, we report an increased frequency of - 10C genotype that is associated with decreased levels of serum alpha1-antitrypsin (alpha 1AT) in COPD patients. The quantification of serum alpha 1AT was done by ELISA, the phenol-chloroform method was used for DNA extraction, PCR products were directly sequenced. The IBM SPSS Statistics v21 software was used for statistical analyses of the data. The mean serum alpha 1AT level was found to be 1.203+0.239 and 3.162+0.160 g/L in COPD cases and in control, respectively. The - 10C allele is associated with an increased risk of COPD [OR, 3.50 (95%CI, 1.86-6.58); p < 0.001]. The combined variant genotype (TT+CC) was significantly found associated with an increased risk of COPD [OR, 3.20 (95% CI, 1.47-6.96); p = 0.003]. A significant association of the family history with COPD (overall p value= 0.0331) suggests that genetics may play an important role in the pathogenesis of COPD. The polymorphism associated with hepatocyte-specific promoter region (- 10T/C) is likely to be associated with the pathogenesis of COPD. It is quite possible that the change of the base in the hepatocyte-specific promoter of the SERPINA1 gene can modulate its strength, thereby driving the reduced expression of alpha 1AT.Department of Biotechnology (DBT), New Delhi: BT/PR7240/MED/30/915/2012; Department of Science and Technology: SB/SO/AS-126/2012; FIST: SR/FST/LSI-384/2008; SAP: F.3-26/2011(SAP-II); UGC: F.3-26/2011(SAP-II

Interactome screening identifies the ER luminal chaperone Hsp47 as a regulator of the unfolded protein response transducer IRE1 alpha

Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). IRE1a is a major UPR transducer, determining cell fate under ER stress. We used an interactome screening to unveil several regulators of the UPR, highlighting the ER chaperone Hsp47 as the major hit. Cellular and biochemical analysis indicated that Hsp47 instigates IRE1 alpha signaling through a physical interaction. Hsp47 directly binds to the ER luminal domain of IRE1 alpha with high affinity, displacing the negative regulator BiP from the complex to facilitate IRE1 alpha oligomerization. The regulation of IRE1 alpha signaling by Hsp47 is evolutionarily conserved as validated using fly and mouse models of ER stress. Hsp47 deficiency sensitized cells and animals to experimental ER stress, revealing the significance of Hsp47 to global proteostasis maintenance. We conclude that Hsp47 adjusts IRE1 alpha signaling by fine-tuning the threshold to engage an adaptive UPR.FONDECYT 1140549 3130365 3150113 3160461 FONDAP program 15150012 Millennium Institute P09-015-F European Commission RD MSCA-RISE 734749 Michael J. Fox Foundation for Parkinson's Research Target Validation grant 9277 FONDEF ID16I10223 D11E1007 US Office of Naval Research Global N62909-16-1-2003 U.S. Air Force Office of Scientific Research FA9550-16-1-0384 ALSRP Therapeutic Idea Award AL150111 Muscular Dystrophy Association 382453 CONICYT-Brazil 441921/2016-7 CONICYT Ph.D. fellowship 21130169 Canadian Institutes of Health research grants MOP-15291 MOP-15415 MOP-53050 INSERM Societe Francophone du Diabete (SFD/MSD) Societe Francaise d'Hepatologie (AFEF/Aptalis) La Ligue contre le Cancer (BMM) French government (National Research Agency, ANR) "Investments for the Future'' LABEX SIGNALIFE ANR-11-LABX-002801 German Research Foundation (DFG) GO 1987/2-1 BNI-P09015

Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1α

© 2018 Elsevier Inc. Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). IRE1α is a major UPR transducer, determining cell fate under ER stress. We used an interactome screening to unveil several regulators of the UPR, highlighting the ER chaperone Hsp47 as the major hit. Cellular and biochemical analysis indicated that Hsp47 instigates IRE1α signaling through a physical interaction. Hsp47 directly binds to the ER luminal domain of IRE1α with high affinity, displacing the negative regulator BiP from the complex to facilitate IRE1α oligomerization. The regulation of IRE1α signaling by Hsp47 is evolutionarily conserved as validated using fly and mouse models of ER stress. Hsp47 deficiency sensitized cells and animals to experimental ER stress, revealing the significance of Hsp47 to global proteostasis maintenance. We conclude that Hsp47 adjusts IRE1α signaling by fine-tuning the threshold to en

Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics

Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we report an unexpected function of the endoplasmic reticulum stress transducer IRE1α as a structural determinant of MAMs that controls mitochondrial calcium uptake. IRE1α deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions. IRE1α determined the distribution of inositol-1,4,5-trisphosphate receptors at MAMs by operating as a scaffold. Using mutagenesis analysis, we separated the housekeeping activity of IRE1α at MAMs from its canonical role in the unfolded protein response. These observations were validated in vivo in the liver of IRE1α conditional knockout mice, revealing broad implications for cellular metabolism. Our results support an alternative function of IRE1α in orchestrating the communication between the endoplasmic reticulum and mitochondria to sustain bioenergetics

IRE1α governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A

© 2018, The Author(s). Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a signalling network known as the unfolded protein response (UPR). Here, we identified filamin A as a major binding partner of the ER stress transducer IRE1α. Filamin A is an actin crosslinking factor involved in cytoskeleton remodelling. We show that IRE1α controls actin cytoskeleton dynamics and affects cell migration upstream of filamin A. The regulation of cytoskeleton dynamics by IRE1α is independent of its canonical role as a UPR mediator, serving instead as a scaffold that recruits and regulates filamin A. Targeting IRE1α expression in mice affected normal brain development, generating a phenotype resembling periventricular heterotopia, a disease linked to the loss of function of filamin A. IRE1α also modulated cell movement and cytoskeleton dynamics in fly and zebrafish models. This study unveils an unanticipated biological function of IRE1α in cell migration, whereby filamin A opera

Publisher Correction: Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics (Nature Cell Biology, (2019), 21, 6, (755-767), 10.1038/s41556-019-0329-y)

An amendment to this paper has been published and can be accessed via a link at the top of the paper