Rubicon controls endosome maturation as a Rab7 effector.
The activation and recruitment of the small GTPase Rab7 to early endosome is a critical step for early to late endosome maturation, a process that requires the class III phosphatidylinositol 3-kinase (PI3KC3) and GTPase regulators. However, the molecular mechanism underlying Rab7 activation and endosome maturation is still poorly defined. Here we report that Rubicon, a component of the PI3KC3 complex, prevents endosome maturation through differential interactions with Rab7 and UVRAG. UVRAG activates PI3KC3 and C-VPS/HOPS, a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on Rab7. We demonstrate that Rubicon sequesters UVRAG from C-VPS/HOPS. Active GTP-bound Rab7 competes for Rubicon binding and releases UVRAG to associate with C-VPS/HOPS, which in turn promotes further loading of Rab7 with GTP. This feed-forward loop ensures rapid amplification of GTP-bound Rab7 and consequent stimulation of endosome maturation. Hence, Rubicon serves as a previously unknown Rab7 effector to ensure the proper progression of the endocytic pathway.
Division of Biochemistry and Molecular Biology, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Qiming
Q
Sun
Wiebke
W
Westphal
Kwun Ngok
KN
Wong
Irena
I
Tan
Qing
Q
Zhong
D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D021381:Protein Transport; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; C552537:RUBCN protein, human; D025521:Tumor Suppressor Proteins; C408122:UVRAG protein, human; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D058539:Phosphatidylinositol 3-Kinase; D020691:rab GTP-Binding Proteins