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PP2A phosphatase inhibition is anti-fibrotic through Ser77 phosphorylation-mediated ARNT/ARNT homodimer formation

Gunsmaa Nyamsuren1, Gregor Rapp1, Hassan Dihazi1

  • 1Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Göttingen, Germany.

Scientific Reports
|December 16, 2021
PubMed

Insights

Aryl hydrocarbon receptor nuclear translocator (ARNT) homodimers combat fibrosis. Targeting Ser77 phosphorylation with LB100 enhances ARNT homodimerization, offering a new therapeutic strategy for kidney and liver fibrosis.

Area of Science:

  • Molecular biology
  • Cellular signaling
  • Fibrosis research

Background:

  • Aryl hydrocarbon receptor nuclear translocator (ARNT) exhibits anti-fibrotic properties in the kidney and liver by upregulating ALK3 receptor expression and Smad1/5/8 signaling.
  • ARNT's therapeutic potential is contingent upon the formation of ARNT-ARNT homodimers, rather than ARNT-AHR or ARNT-HIF1α heterodimers.
  • The precise mechanisms governing ARNT homodimerization specificity and methods to induce it have remained elusive.

Purpose of the Study:

  • To elucidate the molecular mechanisms regulating ARNT homodimer formation.
  • To identify pharmacological strategies for enhancing ARNT-ARNT homodimerization and its anti-fibrotic effects.

Main Methods:

  • Investigated the role of Ser77 phosphorylation in ARNT homodimerization.
  • Utilized in vitro (mouse tubular epithelial cells, human embryonic kidney cells) and in vivo (murine kidney and liver fibrosis models) approaches.
  • Assessed the impact of inhibiting protein phosphatase 2A (PP2A) activity with LB100 on ARNT homodimerization.
  • Evaluated the combined effects of ARNT-inducing agents (FK506, GPI1046) and LB100 on anti-fibrotic activity.

Main Results:

  • Phosphorylation of Ser77 is demonstrated to be critical for the formation and stabilization of ARNT-ARNT homodimers.
  • Inhibition of PP2A phosphatase activity by LB100 significantly enhances ARNT-ARNT homodimer formation both in vitro and in vivo.
  • Combined administration of FK506 or GPI1046 with LB100 resulted in additive anti-fibrotic effects in murine models of kidney and liver fibrosis.

Conclusions:

  • ARNT-ARNT homodimers possess significant anti-fibrotic activity.
  • Ser77 phosphorylation represents a novel pharmacological target for modulating ARNT activity.
  • Targeting Ser77 phosphorylation offers a promising therapeutic avenue to harness the anti-fibrotic potential of ARNT transactivation.

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