Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus

Nadia Jaber, Noor Mohd-Naim, Ziqing Wang, Jennifer L. DeLeon, Seong Kim, Hua Zhong, Namratha Sheshadri, Zhixun Dou, Aimee L. Edinger, Guangwei Du, Vania M.M. Braga, Wei Xing Zong

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

The class III phosphoinositide 3-kinase (PI3K) Vps34 (also known as PIK3C3 in mammals) produces phosphatidylinositol 3-phosphate [PI (3)P] on both early and late endosome membranes to control membrane dynamics. We used Vps34-deficient cells to delineate whether Vps34 has additional roles in endocytic trafficking. In Vps34-/- mouse embryonic fibroblasts (MEFs), transferrin recycling and EEA1 membrane localization were unaffected despite elevated Rab5-GTP levels. Strikingly, a large increase in Rab7-GTP levels, an accumulation of enlarged late endosomes, and decreased EGFR degradation were observed in Vps34-deficient cells. The hyperactivation of Rab7 in Vps34-deficient cells stemmed from the failure to recruit the Rab7 GTPase-activating protein (GAP) Armus (also known as TBC1D2), which binds to PI(3)P, to late endosomes. Protein-lipid overlay and liposome-binding assays reveal that the putative pleckstrin homology (PH) domain in Armus can directly bind to PI(3)P. Elevated Rab7-GTP led to the failure of intraluminal vesicle (ILV) formation and lysosomal maturation. Rab7 silencing and Armus overexpression alleviated the vacuolization seen in Vps34-deficient cells. Taken together, these results demonstrate that Vps34 has a previously unknown role in regulating Rab7 activity and late endosomal trafficking.

Original languageEnglish (US)
Pages (from-to)4424-4435
Number of pages12
JournalJournal of cell science
Volume129
Issue number23
DOIs
StatePublished - 2016

All Science Journal Classification (ASJC) codes

  • Cell Biology

Keywords

  • Armus
  • Endocytosis
  • Rab7
  • Vps34

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