Negative Regulation of TNFR1 Signaling Via PKA-Mediated Phosphorylation of TNFR1

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A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α

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Fatma Zehra Hapil1,2, Fatma Ece Çopuroğlu1, Mustafa Gökhan Ertosun3

  • 1Akdeniz University Department of Medical Biology and Genetics, Antalya, Turkey.

Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research
|March 12, 2020
PubMed

Insights

Protein kinase A (PKA) directly phosphorylates tumor necrosis factor receptor 1 (TNFR1), regulating both canonical and noncanonical signaling pathways. This phosphorylation impacts key cellular responses like apoptosis and immune activation.

Area of Science:

  • Cellular Biology
  • Immunology
  • Molecular Signaling

Background:

  • Tumor necrosis factor alpha (TNF-α) is crucial for immune responses and homeostasis, primarily signaling through TNFR1.
  • Canonical TNFR1 signaling pathways (JNK, p38, NF-κB) leading to apoptosis/necroptosis are established, but noncanonical pathways (ERK, AKT, STAT3) remain less understood.
  • Negative regulation of TNFR1 signaling is largely unknown, despite PKA's known anti-inflammatory roles.

Purpose of the Study:

  • To investigate if PKA directly phosphorylates TNFR1 and modulates its signaling.
  • To determine the role of specific PKA phosphorylation sites (T411, T417) in TNFR1 signaling.
  • To elucidate the impact of PKA-mediated TNFR1 phosphorylation on both canonical and noncanonical pathways.

Main Methods:

  • Identified putative PKA phosphorylation sites (RRRT411, REAT417) in the TNFR1 death domain.
  • Generated alanine and phosphomimetic (aspartic acid) TNFR1 mutants at T411 and T417.
  • Ectopically expressed TNFR1 mutants and assessed TNF-α-induced activation of JNK, p38, ERK, AKT, and STAT3.

Main Results:

  • Demonstrated direct binding and phosphorylation of TNFR1 by PKA upon TNF-α stimulation.
  • Phosphomimetic TNFR1 mutants suppressed TNF-α-induced phosphorylation of ERK, AKT, STAT3, p38α, and JNK1/2.
  • Alanine mutants of TNFR1 at T411 and T417 augmented TNF-α-induced signaling pathway activation.

Conclusions:

  • PKA directly phosphorylates TNFR1 at T411 and T417, acting as a negative regulator.
  • PKA-mediated TNFR1 phosphorylation interferes with both canonical and noncanonical TNF-α signaling pathways.
  • This finding reveals a novel mechanism for controlling TNF-α-driven cellular responses.
Keywords:
AktErkPKATNF-αTNFR1phosphorylation

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