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)

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

Erratum to: IRE1α governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A (Nature Cell Biology, (2018), 20, 8, (942-953), 10.1038/s41556-018-0141-0)

© 2018, The Publisher.In the version of this Article originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Article

Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1 alpha

International audienceMaintenance 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 engage an adaptive UPR

Author Correction: IRE1α governs cytoskeleton remodeling and cell migration through a direct interaction with filamin A

International audienc

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

International audienceIn the version of this Article originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Article

Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response

International audienceThe molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1α signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1α endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1α to catalyze RIDD. The protective role of IRE1α under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis

Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response.

The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1α signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1α endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1α to catalyze RIDD. The protective role of IRE1α under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis