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

Am J Respir Cell Mol Biol. 2021 Nov;65(5):532-543. doi: 10.1165/rcmb.2021-0016OC.

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.

Keywords: cell trafficking; chronic obstructive pulmonary disease; genome-wide association study; network medicine; network validation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Protein Complex 3 / genetics
  • Adaptor Protein Complex 3 / metabolism*
  • Adaptor Protein Complex delta Subunits / genetics
  • Adaptor Protein Complex delta Subunits / metabolism*
  • Cell Line
  • Exosomes / metabolism
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Genome-Wide Association Study
  • HEK293 Cells
  • Humans
  • Protein Interaction Maps / genetics
  • Protein Transport
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Pulmonary Disease, Chronic Obstructive / metabolism*
  • Reproducibility of Results
  • Transforming Growth Factor beta2 / genetics
  • Transforming Growth Factor beta2 / metabolism*

Substances

  • AP3D1 protein, human
  • Adaptor Protein Complex 3
  • Adaptor Protein Complex delta Subunits
  • FAM13A protein, human
  • GTPase-Activating Proteins
  • Transforming Growth Factor beta2