Skip to main content

Transcriptional regulation of lysosomal and autophagosomal biogenesis in muscle cells: implications for Pompe disease

Wednesday, September 24, 2014 — Poster Session IV

10:00 a.m. –12:00 p.m.

FAES Academic Center




  • L. Li
  • G. Gutierrez-Cruz
  • H. Zare
  • N. Raben


Recent studies have established the regulatory role of transcription factor EB (TFEB) in the lysosomal/autophagosomal fusion and exocytosis. We have shown that transcription factor E3 (TFE3) is another master regulator of lysosomal/autophagosomal biogenesis. ChIP-seq in muscle cells identified > 1000 TFE3 direct targets which are similar to known TFEB binding locations. The studies on the regulatory role of TFEB/TFE3 stem from our longstanding interest in Pompe disease, a lysosomal glycogen storage disorder caused by a deficiency of acid alpha glucosidase (GAA). In this severe myopathy, lysosomal glycogen accumulation leads to excessive autophagy and inhibition of the autophagic flux. Autophagic defect is associated with poor muscle response to enzyme replacement therapy. An alternative approach relies on the ability of TFEB and TFE3 to re-establish autophagic flux and induce lysosomal exocytosis in affected muscles. Indeed, overexpression of TFEB or TFE3 in Pompe muscle reduced the lysosomal size, decreased the amount of stored glycogen, and alleviated autophagic accumulation. TFE3 is a more attractive target in Pompe disease due to its abundance in muscle. The number and distribution of TFE3 ChIP-seq peaks in GAA-deficient muscle cells were different from those in controls, thus providing a snapshot of the disease-specific pattern of TFE3-mediated gene regulation.

back to top