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MYPT1-PP1β phosphatase negatively regulates both chromatin landscape and co-activator recruitment for beige

Hiroki Takahashi1,2, Ge Yang1, Takeshi Yoneshiro2

  • 1Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.

Nature Communications
|September 29, 2022
PubMed

Insights

Protein kinase A (PKA) signaling drives beige fat formation. We found that myosin phosphatase target subunit 1- protein phosphatase 1β (MYPT1-PP1β) reverses this by regulating JMJD1A and YAP/TAZ, crucial for energy homeostasis.

Area of Science:

  • Cellular and Molecular Biology
  • Metabolic Regulation
  • Epigenetics

Background:

  • Protein kinase A (PKA) signaling is a key regulator of beige adipogenesis, a process involving the browning of white adipose tissue for thermogenesis.
  • The reversibility of PKA-mediated beige adipogenesis is critical for maintaining energy homeostasis but remains poorly understood at the molecular level.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying the reversal of PKA-driven beige adipogenesis.
  • To identify key proteins and pathways involved in regulating the process and its epigenetic modifications.

Main Methods:

  • Investigated the role of myosin phosphatase target subunit 1- protein phosphatase 1β (MYPT1-PP1β) in beige adipogenesis.
  • Utilized biochemical assays to assess protein phosphorylation and dephosphorylation events.
  • Employed genetic manipulation (Mypt1 deficiency) in pre-adipocytes and mice.
  • Analyzed epigenetic modifications at the Ucp1 enhancer/promoter regions.
  • Examined the activation of YAP/TAZ transcriptional co-activators.

Main Results:

  • PKA-dependent phosphorylation inhibits MYPT1-PP1β activity, leading to increased JMJD1A phosphorylation and enhanced beige adipogenesis.
  • MYPT1-PP1β depletion results in JMJD1A-mediated histone H3 lysine 9 (H3K9) demethylation and activation of Ucp1 gene expression.
  • MYPT1-PP1β dephosphorylates myosin light chain, impacting actomyosin tension and YAP/TAZ activation, which directly drives Ucp1 expression.
  • Mice with pre-adipocyte-specific Mypt1 deficiency exhibit improved cold tolerance and increased Ucp1 levels in subcutaneous white adipose tissue.

Conclusions:

  • Uncovered a regulatory cross-talk mechanism involving MYPT1-PP1β in beige adipogenesis.
  • Demonstrated that MYPT1-PP1β coordinates epigenetic regulation (via JMJD1A) with direct activation of mechano-sensitive YAP/TAZ transcriptional co-activators.
  • Established the in vivo relevance of this pathway for thermogenesis and energy balance.

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