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Functional Characterization of RING-Type E3 Ubiquitin Ligases In Vitro and In Planta
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E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor-mediated antifungal innate immunity

Le-Le Zhu1, Tian-Ming Luo2, Xia Xu3

  • 1Institute for Immunology, Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing 100084, China Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.

The Journal of Experimental Medicine
|July 20, 2016
PubMed

Insights

The Casitas B-lineage lymphoma protein b (Cbl-b) E3 ubiquitin ligase targets activated C-type lectin receptors (CLRs) for degradation, negatively regulating antifungal immunity. Cbl-b deficiency enhances resistance to fungal infections.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • C-type lectin receptors (CLRs) initiate inflammatory responses against microbial infections.
  • The negative regulation mechanisms of activated CLRs are not fully understood.

Purpose of the Study:

  • To investigate the ubiquitination and degradation pathways of activated CLRs.
  • To identify the molecular players involved in CLR negative regulation.

Main Methods:

  • Studied ubiquitination and degradation of Dectin-2 and Dectin-3 in response to fungal infections.
  • Investigated the role of Syk, Cbl-b, and the ESCRT system in CLR regulation.
  • Utilized Cbl-b-deficient mice and wild-type controls for comparative analysis.

Main Results:

  • Activated CLRs Dectin-2 and Dectin-3 undergo Syk-dependent ubiquitination and degradation.
  • E3 ubiquitin ligase Cbl-b mediates CLR ubiquitination via FcR-γ and Syk.
  • The ESCRT system facilitates lysosomal degradation of ubiquitinated CLRs.
  • Cbl-b or ESCRT deficiency leads to increased CLR levels, higher proinflammatory cytokine expression, and enhanced resistance to fungal infections in mice.

Conclusions:

  • Cbl-b negatively regulates CLR-mediated antifungal innate immunity through ubiquitination and degradation.
  • This pathway provides a molecular target for developing novel antifungal therapies.

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