Deritei Dávid, Inuzuka Hiroyuki, Castaldi Peter J, Yun Jeong Hyun, Xu Zhonghui, Anamika Wardatul Jannat, Asara John M, Guo Feng, Zhou Xiaobo, Glass Kimberly, Wei Wenyi, Silverman Edwin K
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, United States.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, United States.
Hum Mol Genet. 2025 Apr 17;34(9):777-789. doi: 10.1093/hmg/ddaf016.
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. The primary causes of COPD are environmental, including cigarette smoking; however, genetic susceptibility also contributes to COPD risk. Genome-Wide Association Studies (GWASes) have revealed more than 80 genetic loci associated with COPD, leading to the identification of multiple COPD GWAS genes. However, the biological relationships between the identified COPD susceptibility genes are largely unknown. Genes associated with a complex disease are often in close network proximity, i.e. their protein products often interact directly with each other and/or similar proteins. In this study, we use affinity purification mass spectrometry (AP-MS) to identify protein interactions with HHIP, a well-established COPD GWAS gene which is part of the sonic hedgehog pathway, in two disease-relevant lung cell lines (IMR90 and 16HBE). To better understand the network neighborhood of HHIP, its proximity to the protein products of other COPD GWAS genes, and its functional role in COPD pathogenesis, we create HUBRIS, a protein-protein interaction network compiled from 8 publicly available databases. We identified both common and cell type-specific protein-protein interactors of HHIP. We find that our newly identified interactions shorten the network distance between HHIP and the protein products of several COPD GWAS genes, including DSP, MFAP2, TET2, and FBLN5. These new shorter paths include proteins that are encoded by genes involved in extracellular matrix and tissue organization. We found and validated interactions to proteins that provide new insights into COPD pathobiology, including CAVIN1 (IMR90) and TP53 (16HBE). The newly discovered HHIP interactions with CAVIN1 and TP53 implicate HHIP in response to oxidative stress.
慢性阻塞性肺疾病（COPD）是全球第三大死因。COPD的主要病因是环境因素，包括吸烟；然而，遗传易感性也会增加患COPD的风险。全基因组关联研究（GWAS）已经揭示了80多个与COPD相关的基因位点，从而确定了多个COPD的GWAS基因。然而，已确定的COPD易感基因之间的生物学关系在很大程度上尚不清楚。与复杂疾病相关的基因通常在网络上紧密相邻，即它们的蛋白质产物经常直接相互作用和/或与相似的蛋白质相互作用。在本研究中，我们使用亲和纯化质谱法（AP-MS）来确定与HHIP的蛋白质相互作用，HHIP是一个已确立的COPD GWAS基因，是音猬因子信号通路的一部分，在两种与疾病相关的肺细胞系（IMR90和16HBE）中进行研究。为了更好地理解HHIP的网络邻域、它与其他COPD GWAS基因的蛋白质产物的接近程度及其在COPD发病机制中的功能作用，我们创建了HUBRIS，这是一个由8个公开可用数据库编译而成的蛋白质-蛋白质相互作用网络。我们确定了HHIP常见的和细胞类型特异性的蛋白质-蛋白质相互作用分子。我们发现，新确定的相互作用缩短了HHIP与几个COPD GWAS基因的蛋白质产物之间的网络距离，这些基因包括DSP、MFAP2、TET2和FBLN5。这些新的较短路径包括由参与细胞外基质和组织组织的基因编码的蛋白质。我们发现并验证了与蛋白质的相互作用，这些相互作用为COPD病理生物学提供了新的见解，包括CAVIN1（IMR90）和TP53（16HBE）。新发现的HHIP与CAVIN1和TP53的相互作用表明HHIP参与了对氧化应激的反应。
