A chronic obstructive pulmonary disease susceptibility gene, FAM13A, regulates protein stability of β-catenin

Rationale: A genetic locus within the FAM13A gene has been consistently associated with chronic obstructive pulmonary disease (COPD)ingenome-wideassociationstudies.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: Fam13anullmice(Fam13a^-/-)weregeneratedandexposed 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 3b 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.