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CRL4DCAF2 negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis

Tao Huang1, Zhengjun Gao1, Yu Zhang2

  • 1Life Sciences Institute, Zhejiang University, Hangzhou, China.

The Journal of Experimental Medicine
|July 19, 2018
PubMed

Insights

The E3 ligase CRL4DCAF2 controls NIK stability, impacting cell cycle and inflammatory diseases. Its inhibition worsens autoimmune conditions, revealing a novel therapeutic target.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • The E3 ligase CRL4DCAF2 is crucial for cell cycle regulation.
  • NEDD8-targeting drugs like MLN4924, which inhibit cullin ring-finger ubiquitin ligases (CRLs), are in clinical trials for cancers.
  • The role of CRL4DCAF2 in myeloid cells and autoimmune diseases is unclear.

Purpose of the Study:

  • To investigate the function of CRL4DCAF2 in dendritic cells (DCs).
  • To elucidate the mechanism by which CRL4DCAF2 regulates NIK and IL-23 production.
  • To determine the role of CRL4DCAF2 in autoimmune disease pathogenesis.

Main Methods:

  • Transcriptomic analysis
  • Immunological assays
  • DCAF2 DC-conditional knockout mouse models

Main Results:

  • CRL4DCAF2 in DCs regulates NIK degradation and negatively controls IL-23 production.
  • CRL4DCAF2 promotes NIK polyubiquitination and degradation independently of TRAF3.
  • DCAF2 deficiency leads to NIK accumulation, RelB nuclear translocation, and increased susceptibility to autoimmune diseases.

Conclusions:

  • CRL4DCAF2 is essential for controlling NIK stability.
  • CRL4DCAF2 plays a critical role in regulating inflammatory responses.
  • This study reveals a novel mechanism for controlling inflammatory diseases via CRL4DCAF2-mediated NIK regulation.

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