Dataset Information

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): Orbitrap Fusion

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

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Dataset's files

Source:

			Action	DRS
	CWF_Comprehensive_Enhanced_Annotation_TMT_PD24_20220308.pdConsensusWF	Other
	CWF_Comprehensive_Enhanced_Annotation_TMT_Quan_PD23cmsp.pdConsensusWF	Other
	Libang_yang_cHenke_17531_CategoryCorrections.pdf	Pdf
	PWF_Fusion_Reporter_Based_Quan_MS2_SequestHT_Percolator.pdProcessingWF	Other
	PWF_Fusion_Reporter_Based_Quan_MS2_SequestHT_TargDec4Scaff.pdProcessingWF	Other

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Publications

SFPQ Promotes Lung Cancer Malignancy <i>via</i> Regulation of CD44 v6 Expression.

Yang Libang L Yang Jianbo J Jacobson Blake B Gilbertsen Adam A Smith Karen K Higgins LeeAnn L Guerrero Candace C Xia Hong H Henke Craig A CA Lin Jizhen J

Frontiers in oncology 20220530

Mesenchymal stem cells (MSCs) contribute to tumor pathogenesis and elicit antitumor immune responses in tumor microenvironments. Nuclear proteins might be the main players in these processes. In the current study, combining spatial proteomics with ingenuity pathway analysis (IPA) in lung non-small cell (NSC) cancer MSCs, we identify a key nuclear protein regulator, SFPQ (Splicing Factor Proline and Glutamine Rich), which is overexpressed in lung cancer MSCs and functions to promote MSCs prolifer ...[more]

PMID: 35707369

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Project description:As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix. Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF?b -driven EMT as one source of IPF myofibroblasts. Keywords: cell type comparison Comparison of lung myofibroblasts from patients with Idiopatic Pulmonary Fibrosis (IPF, 6 donors) to control (6 donors) in contractile and non-contractile matrices using both total and polyribosomal RNA