Dataset Information

Exploring the Spatial Landscape of the Estrogen Receptor Proximal Proteome With Antibody-Based Proximity Labeling

ABSTRACT: Estrogen Receptor-α (ERα) plays a crucial role in breast cancer, driving the transcription of genes involved in tumor progression. The ERα function is dependent on multiple protein-protein interactions (PPIs). As a result of rapid tumor adaptation, these are often altered by drug treatments and acquired mutations. Although elucidating how ERα PPIs evolve in response to therapies is critical to fully uncover drug resistance, capturing transient interactions in their subcellular context remains a major challenge. In this study, we used Biotinylation by Antibody Recognition (BAR) coupled with mass spectrometry to investigate the ERα proximal proteome and its perturbations associated with endocrine resistance.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Graeme Benstead-Hume

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD043294 | Pride | 2024-05-09

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	CR03-01to12_RT10-95min.pdResult	Other
	CR03-01to12_RT10-95min_MasterProteins.xlsx	Xlsx
	CR03-13to18_MasterProteins_Correct.xlsx	Xlsx
	CR03-13to18_fCamC_UniquePeptides.pdResult	Other
	CR03-13to18_fCamC_UniquePeptides.pdResultView	Other

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Exploring the Spatial Landscape of the Estrogen Receptor Proximal Proteome With Antibody-Based Proximity Labeling.

Rega Camilla C Kozik Zuzanna Z Yu Lu L Tsitsa Ifigenia I Martin Lesley-Ann LA Choudhary Jyoti J

Molecular & cellular proteomics : MCP 20231219 1

Estrogen receptor α (ERα) drives the transcription of genes involved in breast cancer (BC) progression, relying on coregulatory protein recruitment for its transcriptional and biological activities. Mutation of ERα as well as aberrant recruitment of its regulatory proteins contribute to tumor adaptation and drug resistance. Therefore, understanding the dynamic changes in ERα protein interaction networks is crucial for elucidating drug resistance mechanisms in BC. Despite progress in studying ERα ...[more]

PMID: 38122900

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Project description:Rapid and dynamically shifting protein-protein interactions (PPIs) underlie the capacity of cells to recognize viral infections and ignite the downstream cascades that constitute the innate-immune response. Herpesviruses share an ancient history of coevolution with their hosts and have developed reciprocal methods to suppress or hijack immune response proteins — underscoring the biological complexity of host-pathogen interactions during the immune response. Accordingly, conventional approaches to studying PPIs downstream of innate immune sensing fail to capture both the global scope and the dynamic on-off behavior of protein complexes as they are altered throughout cellular space and time. To overcome this barrier, we have applied Thermal Proteome Profiling Mass Spectrometry (TPP-MS) to systemically characterize PPIs that coordinate the innate-immune response to Herpes Simplex Virus 1 (HSV-1) infection in primary human fibroblasts. Further, by advancing the power of thermal protein co ggregation analysis (TPCA) to infer associations de novo and to globally track these PPIs, we developed a time-resolved portrait of cellular and viral protein associations with IFI16, a nuclear DNA sensor that serves as a central platform for HSV-1 immune responses. Our TPCA analysis, along with high-resolution microscopy and molecular virological techniques, linked IFI16 sensing of viral DNA in the nuclear periphery to the master DNA damage response (DDR) regulatory kinase, DNA-PK — the activation of which we show to be necessary for the antiviral and inflammatory responses to infection. Finally, phospho-peptide enrichment and MS analysis of DNA-PK substrates revealed IFI16 to be targeted by DNA-PK after both DNA damage and viral infection. Functional analysis of this DDR-dependent IFI16 phosphorylation revealed the specific modified residue required for IFI16-driven cytokine responses. Altogether, our study represents the first systems-wide characterization of the global dynamics of PPIs during HSV-1 infection and uncovers a missing link in the immune signaling pathway that places IFI16 and DNA-PK at the center of herpesvirus innate immunity.