Regulation of Toll-like receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20

Cell Mol Life Sci. 2012 Mar;69(6):963-79. doi: 10.1007/s00018-011-0819-y. Epub 2011 Oct 2.

Abstract

Toll-like receptor (TLR) signaling is linked to autophagy that facilitates elimination of intracellular pathogens. However, it is largely unknown whether autophagy controls TLR signaling. Here, we report that poly(I:C) stimulation induces selective autophagic degradation of the TLR adaptor molecule TRIF and the signaling molecule TRAF6, which is revealed by gene silencing of the ubiquitin-editing enzyme A20. This type of autophagy induced formation of autophagosomes and could be suppressed by an autophagy inhibitor and lysosomal inhibitors. However, this autophagy was not associated with canonical autophagic processes, including involvement of Beclin-1 and conversion of LC3-I to LC3-II. Through screening of TRIF-interacting 'autophagy receptors' in human cells, we identified that NDP52 mediated the selective autophagic degradation of TRIF and TRAF6 but not TRAF3. NDP52 was polyubiquitinated by TRAF6 and was involved in aggregation of TRAF6, which may result in the selective degradation. Intriguingly, only under the condition of A20 silencing, NDP52 could effectively suppress poly(I:C)-induced proinflammatory gene expression. Thus, this study clarifies a selective autophagic mechanism mediated by NDP52 that works downstream of TRIF-TRAF6. Furthermore, although A20 is known as a signaling fine-tuner to prevent excess TLR signaling, it paradoxically downregulates the fine-tuning effect of NDP52 on TLR signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism
  • Autophagy*
  • Cells, Cultured
  • DNA-Binding Proteins
  • Gene Silencing
  • Humans
  • Interferon Regulatory Factor-3 / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / metabolism
  • Nuclear Proteins / physiology*
  • Signal Transduction / physiology*
  • TNF Receptor-Associated Factor 6 / metabolism
  • Toll-Like Receptors / physiology*
  • Tumor Necrosis Factor alpha-Induced Protein 3

Substances

  • Adaptor Proteins, Vesicular Transport
  • CALCOCO2 protein, human
  • DNA-Binding Proteins
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Intracellular Signaling Peptides and Proteins
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Nuclear Proteins
  • TICAM1 protein, human
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3