A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin
Authors: Lester Kobzik
Jane Yu
Francesca Polverino
Michael H Cho
Xiaobo Zhou
Caroline A Owen
Mark A Perrella
Yang Sun
Peter J Castaldi
Augustine M K Choi
Zun Zar Chi Naing
Zhiqiang Jiang
John D Mancini
Weiliang Qiu
Edwin K Silverman
Maria E Laucho-Contreras
Feng Guo
Kushagra Gupta
Taotao Lao
Benjamin A Raby
Journal: American journal of respiratory and critical care medicine (2016)
Discipline: CLINICAL MEDICINE
Keywords: FAM13A; cell proliferation; emphysema; protein stability; β-catenin.
Affiliations: 1 Channing Division of Network Medicine, Department of Medicine., 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine., 3 The Lovelace Respiratory Research Institute, Albuquerque, New Mexico., 4 Division of General Internal Medicine, Department of Medicine, and., 5 Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and., 6 Department of Medicine, Weill Cornell Medical College, New York, New York., 7 Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Abstract:  Rationale: 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. Objectives: 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. Methods: 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. Measurements and main results: 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. Conclusions: We show that FAM13A may influence COPD susceptibility by promoting β-catenin degradation. 

Retracted: No

PubPeer comments:
 Figure 1 and Figure 3 appear to have an image which overlaps, after resizing and differential cropping. From the legends it appears to me that these should be different. Could the authors please check? Apologies if I have misunderstood. *** ![file] *** ![file] ,