Open AccessConnecting COPD GWAS Genes: FAM13A Controls TGFβ2 Secretion by Modulating AP-3 Transport
Author(s) -
Lu Gong,
Sara V. Bates,
Jian Li,
Dandi Qiao,
Kimberly Glass,
Wenyi Wei,
Victor Hsu,
Xiaobo Zhou,
Edwin K. Silverman
Publication year - 2021
Publication title -
american journal of respiratory cell and molecular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.469
H-Index - 161
eISSN - 1535-4989
pISSN - 1044-1549
DOI - 10.1165/rcmb.2021-0016oc
Subject(s) - genome wide association study , biology , ctgf , adamts , copd , signal transducing adaptor protein , genetic association , genetics , computational biology , gene , bioinformatics , microbiology and biotechnology , medicine , single nucleotide polymorphism , receptor , growth factor , metalloproteinase , genotype , thrombospondin , matrix metalloproteinase
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.