ArticleActa pharmacologica Sinica2026
MCOLN1-mediated PPP3CB activation alleviates neuronal damage by promoting TFEB-dependent autophagic flux in permanent cerebral ischemia.
Article in Acta pharmacologica Sinica, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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. Schematic diagram showing how MCOLN1-mediated activation of PPP3CB reduces neuronal damage by promoting TFEB-dependent autophagic flux in permanent cerebral ischemia.
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