title: A mammalian autophagosome maturation mechanism mediated by TECPR1 and the Atg12-Atg5 conjugate.
abstract: Autophagy is a major catabolic pathway in eukaryotes associated with a broad spectrum of human diseases. In autophagy, autophagosomes carrying cellular cargoes fuse with lysosomes for degradation. However, the molecular mechanism underlying autophagosome maturation is largely unknown. Here we report that TECPR1 binds to the Atg12-Atg5 conjugate and phosphatidylinositol 3-phosphate (PtdIns[3]P) to promote autophagosome-lysosome fusion. TECPR1 and Atg16 form mutually exclusive complexes with the Atg12-Atg5 conjugate, and TECPR1 binds PtdIns(3)P upon association with the Atg12-Atg5 conjugate. Strikingly, TECPR1 localizes to and recruits Atg5 to autolysosome membrane. Consequently, elimination of TECPR1 leads to accumulation of autophagosomes and blocks autophagic degradation of LC3-II and p62. Finally, autophagosome maturation marked by GFP-mRFP-LC3 is defective in TECPR1-deficient cells. Thus, we propose that the concerted interactions among TECPR1, Atg12-Atg5, and PtdIns(3)P provide the fusion specificity between autophagosomes and lysosomes and that the assembly of this complex initiates the autophagosome maturation process.
authors.affiliation: Division of Biochemistry, Biophysics, and Structural Biology, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Dandan
authors.initials: D
authors.lastname: Chen
authors.forename: Weiliang
authors.initials: W
authors.lastname: Fan
authors.forename: Yiting
authors.initials: Y
authors.lastname: Lu
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Ding
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhong
mesh_terms: D001343:Autophagy / Q000502:physiology*; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010588:Phagosomes / Q000502:physiology*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C466624:ATG12 protein, human; C502778:ATG5 protein, human; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; C571842:TECPR1 protein, human