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.

慢性阻塞性肺疾病（COPD）是一种常见的复杂疾病，是发病率和死亡率的主要原因。尽管全基因组关联研究 (GWAS) 涉及 COPD 的多个遗传决定因素，但这些关联的病理生理学意义仍然很大程度上未知。从 COPD 蛋白质-蛋白质相互作用网络模块中，我们选择了两个 COPD GWAS 基因之间的网络路径进行验证研究：FAM13A（具有序列相似性 13 成员 A 的家族）-AP3D1-CTGF-TGFβ2。我们发现 TGFβ2、FAM13A 和 AP3D1（但不是 CTGF）形成细胞蛋白复合物。功能表征表明该复合物通过 AP-3（适配蛋白 3）依赖性途径介导 TGFβ2 的分泌，FAM13A 通过靶向这种运输的后期阶段（涉及外套-货物相互作用的解离）充当负调节剂。此外，我们发现 TGFβ2 是一种跨膜蛋白，它与 AP-3 复合物结合，传递到晚期内体隔室，随后通过外泌体分泌。这些结果确定了统一两种 COPD GWAS 蛋白的生物网络作用的病理生理学背景，并揭示了通过细胞内途径进行货物运输的新机制。