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Transcriptional repression of autophagy and lysosome biogenesis

Jaebeom Kim1, Young Suk Yu1, Keun Il Kim2

  • 1Creative Research Initiatives Center for Epigenetic Code and Diseases, School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.

Autophagy
|February 12, 2025
PubMed

Insights

Scientists discovered that upstream transcription factor 2 (USF2) represses autophagy genes under nutrient-rich conditions. Upon nutrient deprivation, transcription factor EB (TFEB) displaces USF2, activating autophagy and lysosomal genes for cellular cleanup.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Genetics

Background:

  • The microphthalmia/transcription factor E (MiT/TFE) family is known to activate autophagy and lysosomal genes during nutrient deficiency.
  • Mechanisms suppressing these genes under nutrient-rich conditions are not well understood.
  • Understanding transcriptional regulation is key to controlling cellular processes like autophagy.

Purpose of the Study:

  • To elucidate the mechanism of transcriptional repression for autophagy and lysosomal genes under nutrient-rich conditions.
  • To identify the key transcription factors and regulatory pathways involved.
  • To explore the therapeutic potential of modulating this pathway.

Main Methods:

  • Investigated the binding of upstream transcription factor 2 (USF2) to the coordinated lysosomal expression and regulation (CLEAR) motif.
  • Analyzed the recruitment of histone deacetylase (HDAC) complexes by USF2.
  • Studied the competitive binding of transcription factor EB (TFEB) to the CLEAR motif.
  • Examined the role of USF2 phosphorylation at serine 155 by glycogen synthase kinase 3 beta (GSK3B).
  • Utilized USF2 knockdown and knockout models.
  • Assessed lysosomal functionality and autophagic flux.
  • Modeled clearance of the SERPINA1 Z variant (antitrypsin Z) in USF2-deficient cells.

Main Results:

  • Identified a novel mechanism where USF2 represses autophagy and lysosomal genes under nutrient-rich conditions by recruiting HDACs to the CLEAR motif.
  • Demonstrated that under nutrient deficiency, TFEB displaces USF2 at the CLEAR motif, activating transcription.
  • Showed that USF2 phosphorylation by GSK3B regulates its DNA binding affinity, controlling the switch between repression and activation.
  • Confirmed that USF2 loss upregulates autophagy/lysosomal genes, enhancing lysosomal function and autophagic flux.
  • Observed rapid clearance of aggregation-prone SERPINA1 Z variant in USF2-deficient cells via the autophagy-lysosome pathway.

Conclusions:

  • USF2 acts as a repressor of autophagy and lysosomal genes under nutrient-rich conditions.
  • TFEB-mediated displacement of USF2 is a key regulatory switch for autophagy activation during nutrient deficiency.
  • Modulating USF2 activity presents a potential therapeutic strategy for diseases linked to impaired autophagy and lysosomal function.
Keywords:
AutophagyMiT/TFETFEBUSF2lysosometranscriptional repressor

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