LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages.

Rémi Pescarmona, Alexandre Belot, Thierry Walzer, Mathias Faure, Yanick J Crow, Thomas Henry, Samir Merabet, Jonathan Reboulet, Francoise Bleicher, Gillian I Rice, Flora Magnotti, Guillaume Sarrabay, Jean-Paul Larbre, Yvan Jamilloux, Sophie Georgin-Lavialle, Ommar Omarjee, Sébastien Viel, Christophe Malcus, Eda Tahir Turanli, Tilmann Kallinich, Agnès Duquesne, Mathieu Gerfaud-Valentin, Cécile Dumaine, Isabelle Melki, Cécile Frachette, Michelle Ainouze, Marion Moreews, Gaëlle Quiniou, Anne-Laure Mathieu

Journal: The Journal of experimental medicine 2021;218(3):e20201006

PMID: 33606008

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Abstract

Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages.

Address: Centre International de Recherche en Infectiologie/International Center for Infectiology Research, Institut National de la Santé et de la Recherche Médicale, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, UMR5308, Lyon, France.; National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, Paris and Lyon, France.; Pediatric Nephrology, Rheumatology, Dermatology Department, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.; General Pediatrics, Infectious Disease and Internal Medicine Department, Hôpital Robert Debre, Assistance Publique-Hôpitaux de Paris, Paris, France.; Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Hôpital Necker, Paris, France.; Internal Medicine, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon, France.; Pediatric Pneumology, Immunology and Intensive Care Medicine, Charité University Medicine Berlin, German Rheumatism Research Center, Leibniz Association, Berlin Institute of Health, Berlin, Germany.; Department of Molecular Biology and Genetics, Faculty of Science and Letters, Istanbul Technical University, Istanbul, Turkey.; Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.; Immunology Department, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.; Immunology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.; Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Sorbonne Université, Service de Médecine Interne, Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses d'Origine Inflammatoire, Paris, France.; Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Université Pierre-et-Marie-Curie-Paris 6, Institut National de la Santé et de la Recherche Médicale UMRS 933, Paris, France.; Rheumatology Unit, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.; Centre Hospitalier Universitaire Montpellier, University of Montpellier, Laboratory of Rare and Autoinflammatory Genetic Diseases and Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses d'Origine Inflammatoire, Montpellier, France.; Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.; Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Lyon, France.; Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

DOI: 10.1084/jem.20201006

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MeSH Terms: Adenylate Kinase, Adolescent, Amino Acid Sequence, Apoptosis, Arthritis, Juvenile, Autophagy, Autophagy-Related Proteins, Bacteria, Cell Differentiation, Child, Exome, Female, Homozygote, Humans, Inflammasomes, Inflammation, Interferons, Intracellular Signaling Peptides and Proteins, Lipid Droplets, Loss of Function Mutation, Lysosomes, Macrophage Colony-Stimulating Factor, Macrophages, Male, Mitochondria, Monocytes, NF-kappa B, Pedigree, Proteomics, Receptors for Activated C Kinase, Signal Transduction, TOR Serine-Threonine Kinases, Young Adult