• Zhiqiang Jiang, Taotao Lao, Weiliang Qiu, Francesca Polverino, Kushagra Gupta, Feng Guo, John D Mancini, Zun Zar Chi Naing, Michael H Cho, Peter J Castaldi, Yang Sun, Jane Yu, Maria E Laucho-Contreras, Lester Kobzik, Benjamin A Raby, Augustine M K Choi, Mark A Perrella, Caroline A Owen, Edwin K Silverman, and Xiaobo Zhou.
• 1 Channing Division of Network Medicine, Department of Medicine.
• Am. J. Respir. Crit. Care Med. 2016 Jul 15; 194 (2): 185197185-97.

RationaleA 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.ObjectivesTo determine the biologic function of FAM13A in human COPD and murine COPD models and discover the molecular mechanism by which FAM13A influences COPD susceptibility.MethodsFam13a 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 ResultsIn 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.ConclusionsWe show that FAM13A may influence COPD susceptibility by promoting β-catenin degradation.

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