HHIP protein interactions in lung cells provide insight into COPD pathogenesis

Area of Science:

• Genomics and Bioinformatics
• Molecular Biology
• Pulmonary Medicine

Background:

• Chronic Obstructive Pulmonary Disease (COPD) is a major global health concern with both environmental and genetic risk factors.
• Genome-Wide Association Studies (GWASes) have identified over 80 genetic loci associated with COPD, but the biological networks connecting these genes remain poorly understood.
• Understanding gene networks is crucial for elucidating complex disease pathogenesis.

Approach:

• Affinity purification mass spectrometry (AP-MS) was employed to identify protein interactions of HHIP, a known COPD GWAS gene within the sonic hedgehog pathway.
• A protein-protein interaction network, HUBRIS, was constructed using 8 public databases to analyze HHIP's network neighborhood and proximity to other COPD GWAS genes.
• Interactions were investigated in two relevant lung cell lines (IMR90 and 16HBE) to identify common and cell-type-specific interactors.

Key Points:

• Newly identified protein interactions for HHIP were discovered, including cell type-specific ones.
• These interactions shorten the network distance between HHIP and other COPD GWAS genes like DSP, MFAP2, TET2, and FBLN5.
• Validated interactions with CAVIN1 (in IMR90 cells) and TP53 (in 16HBE cells) were found, suggesting roles in extracellular matrix organization and oxidative stress response.

Conclusions:

• The study provides novel insights into the functional role of HHIP in COPD pathogenesis by uncovering its protein interaction network.
• The findings highlight the involvement of HHIP in pathways related to extracellular matrix organization and response to oxidative stress.
• This research contributes to a better understanding of the complex genetic architecture of COPD and identifies potential therapeutic targets.