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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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-01246-w |
| _version_ | 1818682109789732864 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-17T10:13:37Z |
| format | Article |
| id | doaj.art-3c1b7fc1246b49098a73e79887c60ae9 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-17T10:13:37Z |
| publishDate | 2017-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-3c1b7fc1246b49098a73e79887c60ae92022-12-21T21:52:57ZengNature PortfolioScientific Reports2045-23222017-04-017111410.1038/s41598-017-01246-wBasal autophagy prevents autoactivation or enhancement of inflammatory signals by targeting monomeric MyD88Takeshi Into0Toshi Horie1Megumi Inomata2Jin Gohda3Jun-ichiro Inoue4Yukitaka Murakami5Shumpei Niida6Department of Oral Microbiology, Division of Oral Infections and Health Sciences, Asahi University School of DentistryDepartment of Oral Microbiology, Division of Oral Infections and Health Sciences, Asahi University School of DentistryDepartment of Oral Microbiology, Division of Oral Infections and Health Sciences, Asahi University School of DentistryResearch Center for Asian Infectious Diseases, The Institute of Medical Science, The University of TokyoDivision of Cellular and Molecular Biology, The Institute of Medical Science, The University of TokyoDepartment of Oral Microbiology, Division of Oral Infections and Health Sciences, Asahi University School of DentistryMedical Genome Center, National Center for Geriatrics and GerontologyAbstract 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.https://doi.org/10.1038/s41598-017-01246-w |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-017-01246-w |
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