title: Atg5 regulates formation of MyD88 condensed structures and MyD88-dependent signal transduction.
abstract: MyD88 is known as an essential adaptor protein for Toll-like receptors (TLRs). Previous studies have shown that transfected MyD88 forms condensed structures in the cytoplasm. However, upon TLR stimulation, there is little formation of endogenous MyD88 condensed structures. Thus, the formation of MyD88 condensed structures is tightly suppressed, but the mechanism and significance of this suppression are currently unknown. Here we show that Atg5, a key regulatory protein of autophagy, inhibits the formation of MyD88 condensed structures. We found that endogenous MyD88 had already formed condensed structures in Atg5-deficient cells and that the formation of condensed structures was further enhanced by TLR stimulation. This suppressive effect of Atg5 may not be associated with autophagic processes because MyD88 itself was not degraded and because TLR stimulation did not induce LC3 punctate formation and LC3 conversion. Immunoprecipitation analysis revealed that Atg5 could interact with MyD88. Furthermore, Atg5 deficiency increased formation of the MyD88-TRAF6 signaling complex induced by TLR stimulation, and it enhanced activation of NF-κB signaling but not MAPKs and Akt. These findings indicate that Atg5 regulates the formation of MyD88 condensed structures through association with MyD88 and eventually exerts a modulatory effect on MyD88-dependent signaling.
authors.affiliation: Department of Oral Microbiology, Division of Oral Infections and Health Sciences, Asahi University School of Dentistry, Mizuho, Gifu, Japan. inomata@dent.asahi-u.ac.jp
authors.forename: Megumi
authors.initials: M
authors.lastname: Inomata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Into
authors.forename: Shumpei
authors.initials: S
authors.lastname: Niida
authors.forename: Yukitaka
authors.initials: Y
authors.lastname: Murakami
mesh_terms: D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
chemical_list: C502778:ATG5 protein, human; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; C507779:MYD88 protein, human; D008869:Microtubule-Associated Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D048029:TNF Receptor-Associated Factor 6
keywords: Autophagy; Condensed structures; MyD88; Signal transduction; Toll-like receptors (TLRs)