PLoS ONE (Jan 2020)

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
https://doi.org/10.1371/journal.pone.0230156
Journal volume & issue
Vol. 15, no. 3
p. e0230156

Abstract

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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.