title: ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis.
abstract: The identification of inflammatory bowel disease (IBD) susceptibility genes by genome-wide association has linked this pathology to autophagy, a lysosomal degradation pathway that is crucial for cell and tissue homeostasis. Here, we describe autophagy-related 4B, cysteine peptidase/autophagin-1 (ATG4B) as an essential protein in the control of inflammatory response during experimental colitis. In this pathological condition, ATG4B protein levels increase in parallel with the induction of autophagy. Moreover, ATG4B expression is significantly reduced in affected areas of the colon from IBD patients. Consistently, atg4b (-/-) mice present Paneth cell abnormalities, as well as an increased susceptibility to DSS-induced colitis. atg4b-deficient mice exhibit significant alterations in proinflammatory cytokines and mediators of the immune response to bacterial infections, which are reminiscent of those found in patients with Crohn disease or ulcerative colitis. Additionally, antibiotic treatments and bone marrow transplantation from wild-type mice reduced colitis in atg4b (-/-) mice. Taken together, these results provided additional evidence for the importance of autophagy in intestinal pathologies and describe ATG4B as a novel protective protein in inflammatory colitis. Finally, we propose that atg4b-null mice are a suitable model for in vivo studies aimed at testing new therapeutic strategies for intestinal diseases associated with autophagy deficiency.
authors.affiliation: Departamento de Bioquímica y Biología Molecular; Facultad de Medicina; Instituto Universitario de Oncología (IUOPA); Universidad de Oviedo; Oviedo, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Cabrera
authors.forename: Alvaro F
authors.initials: AF
authors.lastname: Fernández
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mariño
authors.forename: Alina
authors.initials: A
authors.lastname: Aguirre
authors.forename: María F
authors.initials: MF
authors.lastname: Suárez
authors.forename: Yaiza
authors.initials: Y
authors.lastname: Español
authors.forename: José A
authors.initials: JA
authors.lastname: Vega
authors.forename: Rosaria
authors.initials: R
authors.lastname: Laurà
authors.forename: Antonio
authors.initials: A
authors.lastname: Fueyo
authors.forename: M Soledad
authors.initials: MS
authors.lastname: Fernández-García
authors.forename: José M P
authors.initials: JM
authors.lastname: Freije
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects; D000071183:Autophagy-Related Proteins; D003092:Colitis / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control*; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004198:Disease Susceptibility; D006410:Hematopoiesis / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019879:Paneth Cells / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure
chemical_list: D000900:Anti-Bacterial Agents; D000071183:Autophagy-Related Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D016264:Dextran Sulfate; C582881:Atg4b protein, mouse; D003546:Cysteine Endopeptidases
keywords: ATG4B; Paneth cell; autophagin-1; autophagy; colitis; cysteine peptidase; inflammation; intestinal homeostasis