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

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.

Endothelial protective effect of rapamycin against simulated ischemia injury through up-regulation of autophagy and inhibition of endoplasmic reticulum stress

“…The constitutive active basal autophagy in ECs might contribute to their resistance to ischemia by maintaining the sufficient level of intracellular ATP [8]. Instead, failure of basal autophagy causes the increase in ROS production that activates inflammatory processes and apoptosis [34,35].…”

MyD88 signaling causes autoimmune sialadenitis through formation of high endothelial venules and upregulation of LTβ receptor-mediated signaling

“…MEFs were prepared from 13.5-day embryos from Myd88 +/+ and Myd88 −/− B6 mice and cultured as previously described 59 . MEFs (5 × 10 5 cells) were cultured in 6-well plates and stimulated with 2.5 μg/mL rat anti-mouse LTβR monoclonal antibody 5G11b (low endotoxin product, MCA2244EL; Bio-Rad).…”

Checks and Balances between Autophagy and Inflammasomes during Infection

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