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 o...

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Autores principales:	Takeshi Into, Toshi Horie, Megumi Inomata, Jin Gohda, Jun-ichiro Inoue, Yukitaka Murakami, Shumpei Niida
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3c1b7fc1246b49098a73e79887c60ae9
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spelling	oai:doaj.org-article:3c1b7fc1246b49098a73e79887c60ae92021-12-02T11:40:14ZBasal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD8810.1038/s41598-017-01246-w2045-2322https://doaj.org/article/3c1b7fc1246b49098a73e79887c60ae92017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01246-whttps://doaj.org/toc/2045-2322Abstract 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.Takeshi IntoToshi HorieMegumi InomataJin GohdaJun-ichiro InoueYukitaka MurakamiShumpei NiidaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Takeshi Into Toshi Horie Megumi Inomata Jin Gohda Jun-ichiro Inoue Yukitaka Murakami Shumpei Niida Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88
description	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.
format	article
author	Takeshi Into Toshi Horie Megumi Inomata Jin Gohda Jun-ichiro Inoue Yukitaka Murakami Shumpei Niida
author_facet	Takeshi Into Toshi Horie Megumi Inomata Jin Gohda Jun-ichiro Inoue Yukitaka Murakami Shumpei Niida
author_sort	Takeshi Into
title	Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88
title_short	Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88
title_full	Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88
title_fullStr	Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88
title_full_unstemmed	Basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88
title_sort	basal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric myd88
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/3c1b7fc1246b49098a73e79887c60ae9
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_version_	1718395636619935744

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

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