Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88

Sci Rep. 2017 Apr 21;7(1):1009. doi: 10.1038/s41598-017-01246-w.

Abstract

Autophagy, the processes of delivery of intracellular components to lysosomes, regulates induction of inflammation. Inducible macroautophagy degrades inflammasomes and dysfunctional mitochondria to downregulate inflammatory signals. Nonetheless, the effects of constitutive basal autophagy on inflammatory signals are largely unknown. Here, we report a previously unknown effect of basal autophagy. Lysosomal inhibition induced weak inflammatory signals in the absence of a cellular stimulus and in the presence of a nutrient supply, and their induction was impaired by MyD88 deficiency. During lysosomal inhibition, MyD88 was accumulated, and overabundant MyD88 autoactivated downstream signaling or enhanced TLR/IL-1R-mediated signaling. MyD88 is probably degraded via basal microautophagy because macroautophagy inhibitors, ATG5 deficiency, and an activator of chaperone-mediated autophagy did not affect MyD88. Analysis using a chimeric protein whose monomerization/dimerization can be switched revealed that monomeric MyD88 is susceptible to degradation. Immunoprecipitation of monomeric MyD88 revealed its interaction with TRAF6. In TRAF6-deficient cells, degradation of basal MyD88 was enhanced, suggesting that TRAF6 participates in protection from basal autophagy. Thus, basal autophagy lowers monomeric MyD88 expression, and thereby autoactivation of inflammatory signals is prevented. Given that impairment of lysosomes occurs in various settings, our results provide novel insights into the etiology of inflammatory signals that affect consequences of inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Cells, Cultured
  • Female
  • Inflammasomes / metabolism
  • Lysosomes / metabolism*
  • Male
  • Mice
  • Myeloid Differentiation Factor 88 / chemistry
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism*
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism*

Substances

  • Inflammasomes
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • TNF Receptor-Associated Factor 6
  • Tifab protein, human