title: What else is in store for autophagy? Exocytosis of autolysosomes as a mechanism of TFEB-mediated cellular clearance in Pompe disease.
abstract: It is hard to find an area of biology in which autophagy is not involved. In fact, the topic extends beyond scientific research to stimulate intellectual exercise and entertainment-autophagy has found its way into a crossword puzzle (Klionsky, 2013). We have found yet another function of autophagy while searching for a better treatment for Pompe disease, a devastating metabolic myopathy resulting from excessive lysosomal glycogen storage. To relieve this glycogen burden, we stimulated lysosomal exocytosis through upregulation of transcription factor EB (TFEB). Overexpression of TFEB in Pompe muscle clears the cells of enlarged lysosomes, reduces glycogen levels, and alleviates autophagic buildup, the major secondary abnormality in Pompe disease. Unexpectedly, the process of exocytosis does not seem to be a purely lysosomal event; vesicles arranged along the plasma membrane are double-labeled with the lysosomal marker LAMP1 and the autophagosomal marker LC3, indicating that TFEB induces the exocytosis of autolysosomes. Furthermore, the effects of TFEB are almost abrogated in autophagy-deficient Pompe mice, suggesting a previously unrecognized role of autophagy in TFEB-mediated cellular clearance.
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institutes of Health; Bethesda, MD USA.
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Feeney
authors.forename: Carmine
authors.initials: C
authors.lastname: Spampanato
authors.forename: Rosa
authors.initials: R
authors.lastname: Puertollano
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Parenti
authors.forename: Nina
authors.initials: N
authors.lastname: Raben
mesh_terms: D000818:Animals; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D005089:Exocytosis; D006009:Glycogen Storage Disease Type II / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010588:Phagosomes / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
keywords: Pompe disease; TFEB; acid alpha-glucosidase; lysosomal exocytosis; lysosomal storage