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

Abstract

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.

Phosphoinositides as membrane organizers

“…Increasing formation of intralumenal vesicles results in endosomal maturation to late endosomes/multivesicular bodies and is accompanied by endosomal conversion of RAB5 to RAB7. This depends on the RAB7 GEF MON1–CCZ1 binding to RAB5–GTP to displace Rabex 5 and thereby disrupt the self-perpetuating loop of RAB5 activation 102 , 103 . Effectors of RAB7–GTP characterize the late endosomal compartment and include VPS34 complex II and the retromer complex, ensuring continued PtdIns3P formation and retrieval of cargo 103 .…”

“…This depends on the RAB7 GEF MON1–CCZ1 binding to RAB5–GTP to displace Rabex 5 and thereby disrupt the self-perpetuating loop of RAB5 activation 102 , 103 . Effectors of RAB7–GTP characterize the late endosomal compartment and include VPS34 complex II and the retromer complex, ensuring continued PtdIns3P formation and retrieval of cargo 103 . Late endosomal PtdIns3P serves as a substrate for the PIKfyve complex, a PtdIns3P 5-kinase that is essential for late endosomal and lysosomal function and homeostasis 104 , 105 (see also Table 3 ), as discussed in the following section.…”

The Golgi Apparatus and its Next-Door Neighbors

“…As described above, accumulating evidence indicates that TGN functions as an early endosome. Rab5 is located at PVC and Rab7 is on the vacuole ( Saito and Ueda, 2009 ; Borchers et al, 2021 ). The transition from the Rab5-to the Rab7-compartment has been well investigated not only in mammals but also in yeast and plants ( Rink et al, 2005 ; Sriram et al, 2006 ; Balderhaar and Ungermann, 2013 ; Ebine et al, 2014 ; Takemoto et al, 2018 ; Casler and Glick, 2020 ; Borchers et al, 2021 ).…”

“…Rab5 is located at PVC and Rab7 is on the vacuole ( Saito and Ueda, 2009 ; Borchers et al, 2021 ). The transition from the Rab5-to the Rab7-compartment has been well investigated not only in mammals but also in yeast and plants ( Rink et al, 2005 ; Sriram et al, 2006 ; Balderhaar and Ungermann, 2013 ; Ebine et al, 2014 ; Takemoto et al, 2018 ; Casler and Glick, 2020 ; Borchers et al, 2021 ). A big difference between mammals and plants/fungi is the presence of lysosomes ( de Duve, 1983 ; de Duve, 2005 ).…”

Structure of a TRAPPII-Rab11 activation intermediate reveals GTPase substrate selection mechanisms

“…Protein and membrane traffic in eukaryotic cells is controlled by Rab GTPases that function by recruiting effector protein machinery to generate, transport, and tether membrane vesicles and tubules ( 1, 2 ). Rab1 and Rab11 have been described as the gatekeepers of the Golgi complex ( 3 ).…”