Regulation of Toll-like receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20 |
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Authors: | Megumi?Inomata Shumpei?Niida Ken-ichiro?Shibata Email author" target="_blank">Takeshi?IntoEmail author |
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Institution: | (1) Department of Oral Microbiology, Division of Oral Infections and Health Sciences, Asahi University School of Dentistry, Hozumi 1851, Mizuho, Gifu 501-0296, Japan;(2) Laboratory of Genomics and Proteomics, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522, Japan;(3) Laboratory of Oral Molecular Microbiology, Department of Oral Pathobiological Science, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan; |
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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. |
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