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<p>We previously reported that transcription factor EB (TFEB) plays a crucial role in regulating the ischemic stroke (IS)-mediated dynamic changes of autophagic flux. Protein phosphatase 3 (PPP3) may regulate the transcriptional activity of TFEB. However, the main isoform of the PPP3 catalytic subunit (PPP3C) involved in TFEB activation, the PPP3-binding site in TFEB, and the upstream regulatory mechanism of PPP3 activation after cerebral ischemia are still unknown. Here, we show that the interaction between TFEB and PPP3 catalytic subunit B (PPP3CB), but not PPP3CA, is strengthened after IS. Knockdown of PPP3CB, but not PPP3CA, significantly inhibited the oxygen glucose deprivation (OGD)-induced increase in the transcriptional activity of TFEB, blocked autophagic flux, and exacerbated neuronal death. Furthermore, the YLAVP peptide, which blocks the LxVP motif-binding site of PPP3C, repressed TFEB transcriptional activity and autophagic flux, and exacerbated neuronal death after OGD. Treatment with ML-SI1, which inhibits the lysosomal calcium channel MCOLN1, blocked the OGD-induced enhancement of TFEB transcriptional activity and autophagic flux, and further aggravated neuronal death. These effects were partly reversed by the MCOLN1 agonist ML-SA1. The PPP3 inhibitor cyclosporin A (CsA) abolished the ML-SA1-induced TFEB transcriptional activation and reduced neuronal death. Our findings identify for the first time that MCOLN1-mediated-PPP3CB activation alleviates neuronal damage by promoting TFEB-dependent autophagic flux in permanent cerebral ischemia. The LxVP motif is required for the interaction between PPP3 and TFEB in response to OGD. This study provides an in-depth insight into the mechanisms underlying TFEB-mediated activation of autophagic flux following IS.</p><p></p>

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MCOLN1-mediated PPP3CB activation alleviates neuronal damage by promoting TFEB-dependent autophagic flux in permanent cerebral ischemia

  • 期刊论文

  • 发表日期：

    2026年3月24日

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  • Shi-qi Liu,
  • Yue-yang Liu,
  • Xiao-xiao Fu,
  • Pei-rui Cui,
  • Xin Wang,
  • Sai-qian Wang,
  • Chun-fu Wu,
  • Li-hui Wang,
  • Jing Luo,
  • Jing-yu Yang

摘要

We previously reported that transcription factor EB (TFEB) plays a crucial role in regulating the ischemic stroke (IS)-mediated dynamic changes of autophagic flux. Protein phosphatase 3 (PPP3) may regulate the transcriptional activity of TFEB. However, the main isoform of the PPP3 catalytic subunit (PPP3C) involved in TFEB activation, the PPP3-binding site in TFEB, and the upstream regulatory mechanism of PPP3 activation after cerebral ischemia are still unknown. Here, we show that the interaction between TFEB and PPP3 catalytic subunit B (PPP3CB), but not PPP3CA, is strengthened after IS. Knockdown of PPP3CB, but not PPP3CA, significantly inhibited the oxygen glucose deprivation (OGD)-induced increase in the transcriptional activity of TFEB, blocked autophagic flux, and exacerbated neuronal death. Furthermore, the YLAVP peptide, which blocks the LxVP motif-binding site of PPP3C, repressed TFEB transcriptional activity and autophagic flux, and exacerbated neuronal death after OGD. Treatment with ML-SI1, which inhibits the lysosomal calcium channel MCOLN1, blocked the OGD-induced enhancement of TFEB transcriptional activity and autophagic flux, and further aggravated neuronal death. These effects were partly reversed by the MCOLN1 agonist ML-SA1. The PPP3 inhibitor cyclosporin A (CsA) abolished the ML-SA1-induced TFEB transcriptional activation and reduced neuronal death. Our findings identify for the first time that MCOLN1-mediated-PPP3CB activation alleviates neuronal damage by promoting TFEB-dependent autophagic flux in permanent cerebral ischemia. The LxVP motif is required for the interaction between PPP3 and TFEB in response to OGD. This study provides an in-depth insight into the mechanisms underlying TFEB-mediated activation of autophagic flux following IS.