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OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-Dependent Signaling

Yu Zhao1, Miranda C Mudge1, Jennifer M Soll1

  • 1Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis MO, 63110, USA.

Molecular Cell
|February 4, 2018
PubMed

Insights

The deubiquitinase OTUD4 is activated by phosphorylation to remove K63-linked ubiquitin chains from MyD88, negatively regulating Toll-like receptor (TLR) signaling and NF-κB activation.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Immunology

Background:

  • Ubiquitination regulates key cellular processes like autophagy, DNA damage, and inflammation.
  • While numerous ubiquitin ligases exist, deubiquitinases (DUBs) are less understood, suggesting unknown regulatory mechanisms.
  • The DUB OTUD4 was previously thought to be K48-specific.

Purpose of the Study:

  • To investigate the regulation and substrate specificity of the deubiquitinase OTUD4.
  • To elucidate the role of OTUD4 in Toll-like receptor (TLR) signaling pathways.
  • To understand how post-translational modifications control DUB activity.

Main Methods:

  • Phosphorylation analysis of OTUD4.
  • Biochemical assays to determine K63-linked deubiquitinase activity.
  • Identification of MyD88 as a substrate.
  • Analysis of NF-κB activation in wild-type and Otud4 knockout macrophages.
  • Toll-like receptor stimulation assays.

Main Results:

  • Phosphorylation activates OTUD4's latent K63-specific deubiquitinase activity.
  • A ubiquitin-interacting motif enhances OTUD4's affinity for K63-linked chains.
  • OTUD4 deubiquitinates MyD88, a TLR-associated factor.
  • OTUD4 negatively regulates TLR-mediated NF-κB activation.
  • Otud4-deficient macrophages show heightened inflammatory responses to TLR stimulation.

Conclusions:

  • Post-translational modification (phosphorylation) diversifies deubiquitinase function.
  • OTUD4 acts as a negative regulator of TLR-induced inflammatory signaling.
  • This study reveals a novel mechanism of deubiquitinase regulation and its role in immunity.

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