title: The Inflammatory Bowel Disease-Associated Autophagy GeneAtg16L1T300AActs as a Dominant Negative Variant in Mice.
abstract: The basis of the increased risk for Crohn's disease conferred by theAtg16L1T300Apolymorphism is incompletely understood. An important step forward came from the recent demonstration that the murine equivalent of Atg16L1T300A (Atg16L1T316A) exhibits increased susceptibility to caspase 3-mediated cleavage and resulting decreased levels of full-length Atg16L1 in macrophages. However, although this finding showed that this polymorphism is a loss-of-function abnormality, it did not address the possibility that this polymorphism also affects the function of a normalAtg16L1allele in heterozygous mice. Therefore, we evaluated the function of theAtg16L1T300Apolymorphism heterozygote and homozygote in knock-in (KI) mice. Surprisingly, we found that macrophages from both types of KI mice exhibit defective autophagic induction; accordingly, both types of mice exhibit defects in bacterial clearance coupled with increased inflammasome cytokine (IL-1β) responses. Furthermore, macrophages from both types of KI mice displayed defects in TNF-α-induced Atg16L1T300A cleavage, increased retention of bacteria, bacterial dissemination, andSalmonella-induced colitis. These studies suggested that chromosomes bearing theAtg16L1T300Apolymorphism can interfere with the function of the wild-type (WT)Atg16L1allele and, thus, that the Crohn's disease risk polymorphism is a dominant-negative variant with the potential to act as a disease factor, even when present on only one chromosome. This conclusion was supported by the finding that mice bearing a WTAtg16L1allele and a null allele (Atg16L1KO/+mice) exhibit normal autophagic function equivalent to that of WT mice.
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Huarong
authors.initials: H
authors.lastname: Huang
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Warren
authors.initials: W
authors.lastname: Strober
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; zhangfp@im.ac.cn.|Savaid Medical School, University of Chinese Academy of Sciences, Beijing 101408, China.
authors.forename: Fuping
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins / Q000235:genetics*; D001433:Bacteriolysis / Q000235:genetics; D003092:Colitis / Q000235:genetics* / Q000382:microbiology; D003424:Crohn Disease / Q000235:genetics*; D055879:Gene Knock-In Techniques; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic; D012475:Salmonella / Q000502:physiology*; D012480:Salmonella Infections / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha