title: A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin.
abstract: A genetic locus within the FAM13A gene has been consistently associated with chronic obstructive pulmonary disease (COPD) in genome-wide association studies. However, the mechanisms by which FAM13A contributes to COPD susceptibility are unknown.
  
  
  
  To determine the biologic function of FAM13A in human COPD and murine COPD models and discover the molecular mechanism by which FAM13A influences COPD susceptibility.
  
  
  
  Fam13a null mice (Fam13a(-/-)) were generated and exposed to cigarette smoke. The lung inflammatory response and airspace size were assessed in Fam13a(-/-) and Fam13a(+/+) littermate control mice. Cellular localization of FAM13A protein and mRNA levels of FAM13A in COPD lungs were assessed using immunofluorescence, Western blotting, and reverse transcriptase-polymerase chain reaction, respectively. Immunoprecipitation followed by mass spectrometry identified cellular proteins that interact with FAM13A to reveal insights on FAM13A's function.
  
  
  
  In murine and human lungs, FAM13A is expressed in airway and alveolar type II epithelial cells and macrophages. Fam13a null mice (Fam13a(-/-)) were resistant to chronic cigarette smoke-induced emphysema compared with Fam13a(+/+) mice. In vitro, FAM13A interacts with protein phosphatase 2A and recruits protein phosphatase 2A with glycogen synthase kinase 3β and β-catenin, inducing β-catenin degradation. Fam13a(-/-) mice were also resistant to elastase-induced emphysema, and this resistance was reversed by coadministration of a β-catenin inhibitor, suggesting that FAM13A could increase the susceptibility of mice to emphysema development by inhibiting β-catenin signaling. Moreover, human COPD lungs had decreased protein levels of β-catenin and increased protein levels of FAM13A.
  
  
  
  We show that FAM13A may influence COPD susceptibility by promoting β-catenin degradation.
authors: 1 Channing Division of Network Medicine, Department of Medicine.
authors: Zhiqiang
authors: Z
authors: Jiang
authors: 1 Channing Division of Network Medicine, Department of Medicine.
authors: Taotao
authors: T
authors: Lao
authors: 1 Channing Division of Network Medicine, Department of Medicine.
authors: Weiliang
authors: W
authors: Qiu
authors: 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine.|3 The Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors: Francesca
authors: F
authors: Polverino
authors: 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine.
authors: Kushagra
authors: K
authors: Gupta
authors: 1 Channing Division of Network Medicine, Department of Medicine.
authors: Feng
authors: F
authors: Guo
authors: 1 Channing Division of Network Medicine, Department of Medicine.
authors: John D
authors: JD
authors: Mancini
authors: 1 Channing Division of Network Medicine, Department of Medicine.
authors: Zun Zar Chi
authors: ZZ
authors: Naing
authors: 1 Channing Division of Network Medicine, Department of Medicine.|2 Division of Pulmonary and Critical Care Medicine, Department of Medicine.
authors: Michael H
authors: MH
authors: Cho
authors: 1 Channing Division of Network Medicine, Department of Medicine.|4 Division of General Internal Medicine, Department of Medicine, and.
authors: Peter J
authors: PJ
authors: Castaldi
authors: 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine.
authors: Yang
authors: Y
authors: Sun
authors: 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine.
authors: Jane
authors: J
authors: Yu
authors: 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine.
authors: Maria E
authors: ME
authors: Laucho-Contreras
authors: 5 Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and.
authors: Lester
authors: L
authors: Kobzik
authors: 1 Channing Division of Network Medicine, Department of Medicine.|2 Division of Pulmonary and Critical Care Medicine, Department of Medicine.
authors: Benjamin A
authors: BA
authors: Raby
authors: 6 Department of Medicine, Weill Cornell Medical College, New York, New York.
authors: Augustine M K
authors: AM
authors: Choi
authors: 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine.|7 Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Mark A
authors: MA
authors: Perrella
authors: 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine.|3 The Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors: Caroline A
authors: CA
authors: Owen
authors: 1 Channing Division of Network Medicine, Department of Medicine.|2 Division of Pulmonary and Critical Care Medicine, Department of Medicine.
authors: Edwin K
authors: EK
authors: Silverman
authors: 1 Channing Division of Network Medicine, Department of Medicine.|2 Division of Pulmonary and Critical Care Medicine, Department of Medicine.
authors: Xiaobo
authors: X
authors: Zhou
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055550:Protein Stability; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology*; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D051176:beta Catenin
keywords: FAM13A; cell proliferation; emphysema; protein stability; β-catenin