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Pirin does not bind to p65 or regulate NFκB-dependent gene expression but does modulate cellular quercetin levels.

Melissa Meschkewitz1, Erika M Lisabeth1, Denaly Anna Cab Gomez1

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Pirin protein does not regulate p65 NFκB as previously thought, but its role as a quercetinase is confirmed. Pirin inhibitors increase cellular quercetin levels, suggesting new therapeutic avenues for inflammatory diseases and cancer.

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CCG-257081NFκBPirinQuercetin

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Area of Science:

  • Molecular biology
  • Biochemistry
  • Cell biology

Background:

  • Pirin is an iron-binding protein with proposed roles in NFκB signaling and as a quercetinase.
  • Its precise biological function and mechanism of action remain poorly understood, particularly regarding its interaction with p65 NFκB.
  • Small molecule inhibitors targeting pirin have been identified, but their cellular effects are not fully elucidated.

Purpose of the Study:

  • To investigate the proposed function of pirin as a coactivator of p65 NFκB.
  • To confirm and characterize pirin's quercetinase activity and its implications for cellular quercetin levels.
  • To determine pirin's subcellular localization and its potential role in ER stress.

Main Methods:

  • Analytical size exclusion chromatography and fluorescence polarization to assess protein-protein interactions.
  • Gene transcription assays using pirin knockout and knockdown cell lines.
  • Immunofluorescence microscopy and cell fractionation to determine pirin localization.
  • Biochemical assays to confirm quercetinase activity and inhibition.
  • Analysis of ER stress response genes.

Main Results:

  • No evidence of pirin binding to Fe(III) or interaction with p65 NFκB was detected.
  • Pirin knockdown or knockout did not affect tumor necrosis factor α-induced p65-regulated gene transcription.
  • Pirin predominantly localized to the cytoplasm, co-localizing with the endoplasmic reticulum, contrary to previous reports of nuclear localization.
  • Pirin's quercetinase activity was confirmed, and inhibition of pirin increased cellular quercetin levels.
  • Pirin knockdown did not impact ER stress signaling pathways.

Conclusions:

  • The proposed function of pirin as a nuclear regulator of p65 NFκB is not supported by these findings.
  • Pirin's role as a quercetinase is validated, with implications for modulating cellular quercetin levels.
  • Pirin's cytoplasmic localization, particularly in the ER, suggests alternative biological functions.
  • Pirin-binding compounds may represent a strategy to enhance cellular quercetin, relevant for cancer and inflammatory diseases.