Connecting COPD GWAS Genes: FAM13A Controls TGFβ2 Secretion by Modulating AP-3 Transport

• DOI: 10.1165/rcmb.2021-0016oc
• Publication Date: 2021-06-24T23:21:36Z
• Authors: Lu Gong; Samuel Bates; Jian Li; Dandi Qiao; Kimberly Glass; Wenyi Wei; Victor W. Hsu; Xiaobo Zhou; Edwin K. Silverman
• Keywords: Genome-wide Association Study; ADAMTS; Genetic Association

Chronic obstructive pulmonary disease (COPD) is a common, complex and major cause of morbidity mortality. Although multiple genetic determinants COPD have been implicated by genome-wide association studies (GWASs), the pathophysiological significance these associations remains largely unknown. From protein-protein interaction network module, we selected path between two GWAS genes for validation studies: FAM13A (family with sequence similarity 13 member A)-AP3D1-CTGF- TGFβ2. We find that TGFβ2, FAM13A, AP3D1 (but not CTGF) form cellular protein complex. Functional characterization suggests this mediates secretion TGFβ2 through an AP-3 (adaptor 3)-dependent pathway, acting as negative regulator targeting late stage transport involves dissociation coat-cargo interaction. Moreover, transmembrane engages delivery to endosomal compartments subsequent exosomes. These results identify context unifies biological role proteins reveal novel mechanisms cargo intracellular pathway.