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Deubiquitinases A20 and CYLD modulate costimulatory signaling via CD137 (4-1BB)

Arantza Azpilikueta1, Elixabet Bolaños1, Valerie Lang2

  • 1Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.

Oncoimmunology
|January 4, 2018
PubMed

Insights

Deubiquitinase enzymes A20 and CYLD regulate CD137 (4-1BB) signaling. These enzymes downregulate T-cell costimulation, impacting cancer immunotherapy strategies.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cancer Research

Background:

  • CD137 (4-1BB) receptor stimulation activates NF-κB signaling via TRAF2-dependent K63-polyubiquitinations.
  • Deubiquitinase enzymes (DUBs) are critical regulators of signaling pathways.

Purpose of the Study:

  • To identify DUBs that regulate CD137-mediated signaling.
  • To investigate the role of A20 and CYLD in CD137 signaling and NF-κB activation.

Main Methods:

  • Coimmunoprecipitation assays to detect interactions between CD137, TRAF2, A20, and CYLD.
  • Overexpression and silencing of A20 and CYLD in cell cultures and *in vivo* models.
  • Assessment of TRAF2 and TAK1 ubiquitination levels.
  • Measurement of NF-κB activation and CD8 T cell costimulation.

Main Results:

  • A20 and CYLD were found to interact with CD137 and TRAF2 complexes.
  • Overexpression of A20 or CYLD reduced CD137-induced ubiquitination of TRAF2 and TAK1.
  • A20 and CYLD suppressed CD137-induced NF-κB activation *in vitro* and *in vivo*.
  • Silencing A20 and CYLD enhanced CD137 costimulation of human CD8 T cells.

Conclusions:

  • A20 and CYLD directly downregulate signaling from the CD137 costimulatory receptor.
  • These findings have implications for optimizing CD137-based cancer immunotherapy.
Keywords:
A20CD137(41BB)CYLDDeubiquitinasesTRAF2

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