Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex

J Cell Biol. 2021 Feb 1;220(2):e202002075. doi: 10.1083/jcb.202002075.


Adaptor protein complex 5 (AP-5) and its partners, SPG11 and SPG15, are recruited onto late endosomes and lysosomes. Here we show that recruitment of AP-5/SPG11/SPG15 is enhanced in starved cells and occurs by coincidence detection, requiring both phosphatidylinositol 3-phosphate (PI3P) and Rag GTPases. PI3P binding is via the SPG15 FYVE domain, which, on its own, localizes to early endosomes. GDP-locked RagC promotes recruitment of AP-5/SPG11/SPG15, while GTP-locked RagA prevents its recruitment. Our results uncover an interplay between AP-5/SPG11/SPG15 and the mTORC1 pathway and help to explain the phenotype of AP-5/SPG11/SPG15 deficiency in patients, including the defect in autophagic lysosome reformation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Endosomes / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Models, Biological
  • Monomeric GTP-Binding Proteins / metabolism*
  • Multiprotein Complexes / metabolism*
  • Nucleotides / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol Phosphates / metabolism*
  • Protein Domains
  • Proteins / metabolism*


  • Adaptor Proteins, Vesicular Transport
  • Carrier Proteins
  • Multiprotein Complexes
  • Nucleotides
  • Phosphatidylinositol Phosphates
  • Proteins
  • SPG11 protein, human
  • ZFYVE26 protein, human
  • phosphatidylinositol 3-phosphate
  • PIKFYVE protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Monomeric GTP-Binding Proteins