Starvation-induced autophagy via calcium-dependent TFEB dephosphorylation is suppressed by Shigyakusan
Identifieur interne : 000045 ( Main/Exploration ); précédent : 000044; suivant : 000046Starvation-induced autophagy via calcium-dependent TFEB dephosphorylation is suppressed by Shigyakusan
Auteurs : Sumiko Ikari [Japon] ; Shiou-Ling Lu [Japon] ; Feike Hao [Japon, République populaire de Chine] ; Kenta Imai [Japon] ; Yasuhiro Araki [Japon] ; Yo-Hei Yamamoto [Japon] ; Chao-Yuan Tsai [Japon] ; Yumi Nishiyama [Japon] ; Nobukazu Shitan [Japon] ; Tamotsu Yoshimori [Japon] ; Takanobu Otomo [Japon] ; Takeshi Noda [Japon]Source :
- PLoS ONE [ 1932-6203 ] ; 2020.
Abstract
Kampo, a system of traditional Japanese therapy utilizing mixtures of herbal medicine, is widely accepted in the Japanese medical system. Kampo originated from traditional Chinese medicine, and was gradually adopted into a Japanese style. Although its effects on a variety of diseases are appreciated, the underlying mechanisms remain mostly unclear. Using a quantitative tf-LC3 system, we conducted a high-throughput screen of 128 kinds of Kampo to evaluate the effects on autophagy. The results revealed a suppressive effect of Shigyakusan/TJ-35 on autophagic activity. TJ-35 specifically suppressed dephosphorylation of ULK1 and TFEB, among several TORC1 substrates, in response to nutrient deprivation. TFEB was dephosphorylated by calcineurin in a Ca2+ dependent manner. Cytosolic Ca2+ concentration was increased in response to nutrient starvation, and TJ-35 suppressed this increase. Thus, TJ-35 prevents the starvation-induced Ca2+ increase, thereby suppressing induction of autophagy.
Url:
DOI: 10.1371/journal.pone.0230156
PubMed: 32134989
PubMed Central: 7058311
Affiliations:
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uniqKey="Tsai C" first="Chao-Yuan" last="Tsai">Chao-Yuan Tsai</name><affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation></author><author><name sortKey="Nishiyama, Yumi" sort="Nishiyama, Yumi" uniqKey="Nishiyama Y" first="Yumi" last="Nishiyama">Yumi Nishiyama</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Medicinal Botanical Garden, Kobe Pharmaceutical University, Kobe, Hyogo, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Medicinal Botanical Garden, Kobe Pharmaceutical University, Kobe, 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Shigyakusan</title><author><name sortKey="Ikari, Sumiko" sort="Ikari, Sumiko" uniqKey="Ikari S" first="Sumiko" last="Ikari">Sumiko Ikari</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Center for Frontier Oral Science, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Center for Frontier Oral Science, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation></author><author><name sortKey="Lu, Shiou Ling" sort="Lu, Shiou Ling" uniqKey="Lu S" first="Shiou-Ling" last="Lu">Shiou-Ling Lu</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation></author><author><name sortKey="Hao, Feike" sort="Hao, Feike" uniqKey="Hao F" first="Feike" last="Hao">Feike Hao</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>China National Research Institute of Food and Fermentation Industries, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>China National Research Institute of Food and Fermentation Industries, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Imai, Kenta" sort="Imai, Kenta" uniqKey="Imai K" first="Kenta" last="Imai">Kenta Imai</name><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation></author><author><name sortKey="Araki, Yasuhiro" sort="Araki, Yasuhiro" uniqKey="Araki Y" first="Yasuhiro" last="Araki">Yasuhiro Araki</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation></author><author><name sortKey="Yamamoto, Yo Hei" sort="Yamamoto, Yo Hei" uniqKey="Yamamoto Y" first="Yo-Hei" last="Yamamoto">Yo-Hei Yamamoto</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation></author><author><name sortKey="Tsai, Chao Yuan" sort="Tsai, Chao Yuan" uniqKey="Tsai C" first="Chao-Yuan" last="Tsai">Chao-Yuan Tsai</name><affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation></author><author><name sortKey="Nishiyama, Yumi" sort="Nishiyama, Yumi" uniqKey="Nishiyama Y" first="Yumi" last="Nishiyama">Yumi Nishiyama</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Medicinal Botanical Garden, Kobe Pharmaceutical University, Kobe, Hyogo, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Medicinal Botanical Garden, Kobe Pharmaceutical University, Kobe, Hyogo</wicri:regionArea><wicri:noRegion>Hyogo</wicri:noRegion></affiliation></author><author><name sortKey="Shitan, Nobukazu" sort="Shitan, Nobukazu" uniqKey="Shitan N" first="Nobukazu" last="Shitan">Nobukazu Shitan</name><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Laboratory of Medicinal Cell Biology, Kobe Pharmaceutical University, Kobe, Hyogo, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Medicinal Cell Biology, Kobe Pharmaceutical University, Kobe, Hyogo</wicri:regionArea><wicri:noRegion>Hyogo</wicri:noRegion></affiliation></author><author><name sortKey="Yoshimori, Tamotsu" sort="Yoshimori, Tamotsu" uniqKey="Yoshimori T" first="Tamotsu" last="Yoshimori">Tamotsu Yoshimori</name><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation></author><author><name sortKey="Otomo, Takanobu" sort="Otomo, Takanobu" uniqKey="Otomo T" first="Takanobu" last="Otomo">Takanobu Otomo</name><affiliation wicri:level="1"><nlm:aff id="aff008"><addr-line>Department of Molecular and Genetic Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Molecular and Genetic Medicine, Kawasaki Medical School, Kurashiki, Okayama</wicri:regionArea><wicri:noRegion>Okayama</wicri:noRegion></affiliation></author><author><name sortKey="Noda, Takeshi" sort="Noda, Takeshi" uniqKey="Noda T" first="Takeshi" last="Noda">Takeshi Noda</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Center for Frontier Oral Science, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Center for Frontier Oral Science, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Kampo, a system of traditional Japanese therapy utilizing mixtures of herbal medicine, is widely accepted in the Japanese medical system. Kampo originated from traditional Chinese medicine, and was gradually adopted into a Japanese style. Although its effects on a variety of diseases are appreciated, the underlying mechanisms remain mostly unclear. Using a quantitative tf-LC3 system, we conducted a high-throughput screen of 128 kinds of Kampo to evaluate the effects on autophagy. The results revealed a suppressive effect of Shigyakusan/TJ-35 on autophagic activity. TJ-35 specifically suppressed dephosphorylation of ULK1 and TFEB, among several TORC1 substrates, in response to nutrient deprivation. TFEB was dephosphorylated by calcineurin in a Ca<sup>2+</sup> dependent manner. Cytosolic Ca<sup>2+</sup> concentration was increased in response to nutrient starvation, and TJ-35 suppressed this increase. Thus, TJ-35 prevents the starvation-induced Ca<sup>2+</sup> increase, thereby suppressing induction of autophagy.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Mizushima, N" uniqKey="Mizushima N">N. 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uniqKey="Nishiyama Y" first="Yumi" last="Nishiyama">Yumi Nishiyama</name><name sortKey="Noda, Takeshi" sort="Noda, Takeshi" uniqKey="Noda T" first="Takeshi" last="Noda">Takeshi Noda</name><name sortKey="Noda, Takeshi" sort="Noda, Takeshi" uniqKey="Noda T" first="Takeshi" last="Noda">Takeshi Noda</name><name sortKey="Otomo, Takanobu" sort="Otomo, Takanobu" uniqKey="Otomo T" first="Takanobu" last="Otomo">Takanobu Otomo</name><name sortKey="Shitan, Nobukazu" sort="Shitan, Nobukazu" uniqKey="Shitan N" first="Nobukazu" last="Shitan">Nobukazu Shitan</name><name sortKey="Tsai, Chao Yuan" sort="Tsai, Chao Yuan" uniqKey="Tsai C" first="Chao-Yuan" last="Tsai">Chao-Yuan Tsai</name><name sortKey="Yamamoto, Yo Hei" sort="Yamamoto, Yo Hei" uniqKey="Yamamoto Y" first="Yo-Hei" last="Yamamoto">Yo-Hei Yamamoto</name><name sortKey="Yoshimori, Tamotsu" sort="Yoshimori, Tamotsu" uniqKey="Yoshimori T" first="Tamotsu" last="Yoshimori">Tamotsu Yoshimori</name></country><country name="République populaire de 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