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MKP-1 modulates ubiquitination/phosphorylation of TLR signaling

Jaya Talreja1, Christian Bauerfeld2, Xiantao Wang3

  • 1Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI, USA.

Life Science Alliance
|September 28, 2021
PubMed

Insights

Mitogen-activated protein kinase phosphatase (MKP)-1 deficiency alters deubiquitinase enzymes, impacting immune signaling. Inhibiting USP13 reduces TRAF6 ubiquitination and inflammatory responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is crucial for regulating innate and adaptive immunity.
  • MKP-1's known function involves dephosphorylating p38 and JNK MAPKs.
  • Its broader roles in immune cell regulation are not fully understood.

Purpose of the Study:

  • To investigate the role of MKP-1 in modulating ubiquitin ligases and deubiquitinase enzymes (DUBs).
  • To elucidate the impact of MKP-1 deficiency on IL-1/Toll-like receptor (TLR) signaling pathways.
  • To identify specific DUBs regulated by MKP-1 and their downstream effects.

Main Methods:

  • Comparative analysis of gene and protein expression in wild-type and MKP-1 knockout (MKP-1-/-) murine bone marrow-derived macrophages (BMDMs).
  • Assessment of protein ubiquitination status, particularly K63 polyubiquitination on TRAF6.
  • Pharmacological inhibition of ubiquitin-specific protease-13 (USP13) to evaluate its effect on signaling pathways and cytokine production.

Main Results:

  • MKP-1 deficiency leads to aberrant regulation of DUBs and increased expression of IL-1/TLR signaling components.
  • MKP-1-/- BMDMs exhibit enhanced K63 polyubiquitination on TRAF6 and increased TAK1 phosphorylation.
  • USP13 expression is substantially enhanced in MKP-1-deficient BMDMs, and its inhibition reduces TRAF6 ubiquitination and inflammatory cytokine induction.

Conclusions:

  • MKP-1 influences the ubiquitin ligase activity of TRAF6 through the modulation of specific DUBs, notably USP13.
  • This study reveals a novel mechanism by which MKP-1 controls inflammatory signaling pathways.
  • Targeting USP13 may represent a therapeutic strategy for inflammatory conditions associated with MKP-1 dysregulation.

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