Journal Article

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

Gong, Lu, Zhou, Xiaobo, Bates, Samuel, Silverman, Edwin K., Wei, Wenyi, Qiao, Dandi, Hsu, Victor W., Li, Jian, Glass, Kimberly

2021

Overview

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

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Adaptor Protein Complex 3 - genetics / Adaptor Protein Complex 3 - metabolism / Adaptor Protein Complex delta Subunits - genetics / Adaptor Protein Complex delta Subunits - metabolism / AP-3 protein / Cell Line / Chronic obstructive pulmonary disease / Connective tissue growth factor / Exosomes - metabolism / Genes / Genome-wide association studies / Genome-Wide Association Study / Genomes / GTPase-Activating Proteins - genetics / GTPase-Activating Proteins - metabolism / HEK293 Cells / Humans / Lung diseases / Morbidity / Obstructive lung disease / Original Research / Protein Interaction Maps - genetics / Protein Transport / Proteins / Pulmonary Disease, Chronic Obstructive - genetics / Pulmonary Disease, Chronic Obstructive - metabolism / Reproducibility of Results / Secretion / Transforming Growth Factor beta2 - genetics / Transforming Growth Factor beta2 - metabolism