Who's in control? Principles of Rab GTPase activation in endolysosomal membrane trafficking and beyond

J Cell Biol. 2021 Sep 6;220(9):e202105120. doi: 10.1083/jcb.202105120. Epub 2021 Aug 12.


The eukaryotic endomembrane system consists of multiple interconnected organelles. Rab GTPases are organelle-specific markers that give identity to these membranes by recruiting transport and trafficking proteins. During transport processes or along organelle maturation, one Rab is replaced by another, a process termed Rab cascade, which requires at its center a Rab-specific guanine nucleotide exchange factor (GEF). The endolysosomal system serves here as a prime example for a Rab cascade. Along with endosomal maturation, the endosomal Rab5 recruits and activates the Rab7-specific GEF Mon1-Ccz1, resulting in Rab7 activation on endosomes and subsequent fusion of endosomes with lysosomes. In this review, we focus on the current idea of Mon1-Ccz1 recruitment and activation in the endolysosomal and autophagic pathway. We compare identified principles to other GTPase cascades on endomembranes, highlight the importance of regulation, and evaluate in this context the strength and relevance of recent developments in in vitro analyses to understand the underlying foundation of organelle biogenesis and maturation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Autophagosomes / genetics
  • Autophagosomes / metabolism*
  • Biological Transport
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Conserved Sequence
  • Endosomes / genetics
  • Endosomes / metabolism*
  • Gene Expression Regulation
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Lysosomes / genetics
  • Lysosomes / metabolism*
  • Organelle Biogenesis*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Signal Transduction
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*
  • rab5 GTP-Binding Proteins / genetics
  • rab5 GTP-Binding Proteins / metabolism*
  • rab7 GTP-Binding Proteins


  • Ccz1 protein, S cerevisiae
  • Guanine Nucleotide Exchange Factors
  • Mon1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Vesicular Transport Proteins
  • rab7 GTP-Binding Proteins
  • rab7 GTP-binding proteins, human
  • rab GTP-Binding Proteins
  • rab5 GTP-Binding Proteins