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Inositol Polyphosphate Multikinase Inhibits Liquid-Liquid Phase Separation of TFEB to Negatively Regulate Autophagy
Di Chen1, Zheng Wang2, Yan G Zhao3
1National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, P.R. China.
Abstract:
Liquid-liquid phase separation (LLPS) compartmentalizes transcriptional condensates for gene expression, but little is known about how this process is controlled. Here, we showed that depletion of IPMK, encoding inositol polyphosphate multikinase, promotes autophagy and lysosomal function and biogenesis in a TFEB-dependent manner. Cytoplasmic-nuclear trafficking of TFEB, a well-characterized mechanism by which diverse signaling pathways regulate TFEB activity, is not evidently altered by IPMK depletion. We demonstrated that nuclear TFEB forms distinct puncta that colocalize with the Mediator complex and with mRNAs of target lysosomal genes. TFEB undergoes LLPS in vitro. IPMK directly interacts with and inhibits LLPS of TFEB and also dissolves TFEB condensates. Depletion of IPMK increases the number of nuclear TFEB puncta and the co-localization of TFEB with Mediator and mRNAs of target genes. Our study reveals that nuclear-localized IPMK acts as a chaperone to inhibit LLPS of TFEB to negatively control its transcriptional activity.
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