Starvation-induced autophagy via calcium-dependent TFEB dephosphorylation is suppressed by Shigyakusan

Sumiko Ikari; Shiou-Ling Lu; Feike Hao; Kenta Imai; Yasuhiro Araki; Yo-Hei Yamamoto; Chao-Yuan Tsai; Yumi Nishiyama; Nobukazu Shitan; Tamotsu Yoshimori; Takanobu Otomo; Takeshi Noda

doi:10.1371/journal.pone.0230156

Starvation-induced autophagy via calcium-dependent TFEB dephosphorylation is suppressed by Shigyakusan

PLoS One. 2020 Mar 5;15(3):e0230156. doi: 10.1371/journal.pone.0230156. eCollection 2020.

Authors

Sumiko Ikari¹, Shiou-Ling Lu², Feike Hao^{2

3}, Kenta Imai⁴, Yasuhiro Araki², Yo-Hei Yamamoto², Chao-Yuan Tsai⁵, Yumi Nishiyama⁶, Nobukazu Shitan⁷, Tamotsu Yoshimori⁴, Takanobu Otomo⁸, Takeshi Noda^{1

2}

Affiliations

¹ Center for Frontier Oral Science, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
² Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.
³ China National Research Institute of Food and Fermentation Industries, Beijing, China.
⁴ Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
⁵ Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
⁶ Medicinal Botanical Garden, Kobe Pharmaceutical University, Kobe, Hyogo, Japan.
⁷ Laboratory of Medicinal Cell Biology, Kobe Pharmaceutical University, Kobe, Hyogo, Japan.
⁸ Department of Molecular and Genetic Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy / drug effects*
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / drug effects*
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
Calcineurin / metabolism
Calcium / metabolism
Drugs, Chinese Herbal / pharmacology*
Humans
Mechanistic Target of Rapamycin Complex 1 / metabolism
Phosphorylation
Starvation / metabolism

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Drugs, Chinese Herbal
TFEB protein, human
shigyaku-san
Mechanistic Target of Rapamycin Complex 1
Calcineurin
Calcium

Grants and funding

Takeshi NODA has received research grant from Tsumura CO. LTD. Tsumura CO LTD has no role in the study design; collection, analysis, and interpretation of data; writing of the paper; and decision to submit for publication.