Proteomic Analysis of the IPF Mesenchymal Progenitor Cell Nuclear Proteome Identifies Abnormalities in Key Nodal Proteins That Underlie Their Fibrogenic Phenotype

ABSTRACT: IPF is a progressive fibrotic lung disease whose pathogenesis remains incompletely understood. We have previously discovered pathologic mesenchymal progenitor cells (MPCs) in the lungs of IPF patients. IPF MPCs display a distinct transcriptome and create sustained interstitial fibrosis in immune deficient mice. However, the precise pathologic alterations responsible for this fibrotic phenotype remain to be uncovered. Quantitative mass spectrometry and interactomics is a powerful tool that can define protein alterations in specific subcellular compartments that can be implemented to understand disease pathogenesis. We employed quantitative mass spectrometry and interactomics to define protein alterations in the nuclear compartment of IPF MPCs. We identified increased nuclear levels of PARP1, CDK1, and BACH1. Interactomics implicated PARP1, CDK1, and BACH1 as key hub proteins in the DNA damage/repair, differentiation, and apoptosis signaling pathways respectively. Loss of function and inhibitor studies demonstrated important roles for PARP1 in DNA damage/repair, CDK1 in regulating IPF MPC stemness and self-renewal, and BACH1 in regulating IPF MPC viability. Quantitative mass spectrometry combined with interactomics is a powerful tool for defining alterations in key proteins important in uncovering disease mechanisms.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Fibroblast

DISEASE(S): Idiopathic Pulmonary Fibrosis

SUBMITTER: Adam Gilbertsen  

LAB HEAD: Craig Henke

PROVIDER: PXD032352 | Pride | 2022-08-12

REPOSITORIES: Pride