The Ubiquitin-Modifying Enzyme A20 Terminates C-Type Lectin Receptor Signals and Is a Suppressor of Host Defense against Systemic Fungal Infection

Infect Immun. 2020 Aug 19;88(9):e00048-20. doi: 10.1128/IAI.00048-20. Print 2020 Aug 19.

Abstract

C-type lectin receptors (CLRs) play key roles in antifungal defense. CLR-induced NF-κB is central to CLR functions in immunity, and thus, molecules that control the amplitude of CLR-induced NF-κB could profoundly influence host defense against fungal pathogens. However, little is known about the mechanisms that negatively regulate CLR-induced NF-κB, and molecules which act on the CLR family broadly and which directly regulate acute CLR-signaling cascades remain unidentified. Here, we identify the ubiquitin-editing enzyme A20 as a negative regulator of acute NF-κB activation downstream of multiple CLR pathways. Absence of A20 suppression results in exaggerated CLR responses in cells which are A20 deficient and also cells which are A20 haplosufficient, including multiple primary immune cells. Loss of a single allele of A20 results in enhanced defense against systemic Candida albicans infection and prolonged host survival. Thus, A20 restricts CLR-induced innate immune responses in vivo and is a suppressor of host defense against systemic fungal infection.

Keywords: A20; C-type lectin receptors; NF-κB; TRAF6; cytokines; dendritic cells; fungal immunity; innate immunity; ubiquitination.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / microbiology
  • Candida albicans / immunology*
  • Candida albicans / pathogenicity
  • Candidiasis / genetics
  • Candidiasis / immunology*
  • Candidiasis / microbiology
  • Dendritic Cells / immunology
  • Dendritic Cells / microbiology
  • Female
  • Fetus
  • Host Microbial Interactions / genetics
  • Host Microbial Interactions / immunology*
  • Immunity, Innate
  • Lectins, C-Type / genetics
  • Lectins, C-Type / immunology*
  • Liver / immunology
  • Liver / microbiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / immunology
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Primary Cell Culture
  • Protein Processing, Post-Translational*
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / immunology
  • Tumor Necrosis Factor alpha-Induced Protein 3 / deficiency
  • Tumor Necrosis Factor alpha-Induced Protein 3 / genetics
  • Tumor Necrosis Factor alpha-Induced Protein 3 / immunology*
  • Ubiquitin / genetics
  • Ubiquitin / immunology
  • Ubiquitination

Substances

  • Lectins, C-Type
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • TNF Receptor-Associated Factor 6
  • TRAF6 protein, mouse
  • Ubiquitin
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Tnfaip3 protein, mouse