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Review
. 2021 Jun 24:9:698190.
doi: 10.3389/fcell.2021.698190. eCollection 2021.

RAVE and Rabconnectin-3 Complexes as Signal Dependent Regulators of Organelle Acidification

Michael C Jaskolka  1 , Samuel R Winkley  1 , Patricia M Kane  1
Affiliations
Review

RAVE and Rabconnectin-3 Complexes as Signal Dependent Regulators of Organelle Acidification

Michael C Jaskolka et al. Front Cell Dev Biol. .

Abstract

The yeast RAVE (Regulator of H+-ATPase of Vacuolar and Endosomal membranes) complex and Rabconnectin-3 complexes of higher eukaryotes regulate acidification of organelles such as lysosomes and endosomes by catalyzing V-ATPase assembly. V-ATPases are highly conserved proton pumps consisting of a peripheral V1 subcomplex that contains the sites of ATP hydrolysis, attached to an integral membrane V o subcomplex that forms the transmembrane proton pore. Reversible disassembly of the V-ATPase is a conserved regulatory mechanism that occurs in response to multiple signals, serving to tune ATPase activity and compartment acidification to changing extracellular conditions. Signals such as glucose deprivation can induce release of V1 from Vo, which inhibits both ATPase activity and proton transport. Reassembly of V1 with Vo restores ATP-driven proton transport, but requires assistance of the RAVE or Rabconnectin-3 complexes. Glucose deprivation triggers V-ATPase disassembly in yeast and is accompanied by binding of RAVE to V1 subcomplexes. Upon glucose readdition, RAVE catalyzes both recruitment of V1 to the vacuolar membrane and its reassembly with Vo. The RAVE complex can be recruited to the vacuolar membrane by glucose in the absence of V1 subunits, indicating that the interaction between RAVE and the Vo membrane domain is glucose-sensitive. Yeast RAVE complexes also distinguish between organelle-specific isoforms of the Vo a-subunit and thus regulate distinct V-ATPase subpopulations. Rabconnectin-3 complexes in higher eukaryotes appear to be functionally equivalent to yeast RAVE. Originally isolated as a two-subunit complex from rat brain, the Rabconnectin-3 complex has regions of homology with yeast RAVE and was shown to interact with V-ATPase subunits and promote endosomal acidification. Current understanding of the structure and function of RAVE and Rabconnectin-3 complexes, their interactions with the V-ATPase, their role in signal-dependent modulation of organelle acidification, and their impact on downstream pathways will be discussed.

Keywords: DMXL2; RAVE = regulator of H+-ATPase of vacuoles and endosomes; Rabconnectin-3; V-ATPase; WDR7; endosome and lysosome; organelle acidification; vacuole.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
V-ATPase structural model. V-ATPases consist of a peripheral V1 complex and an integral membrane Vo complex, both containing multiple subunits. The V1 complex contains a hexamer of catalytic and regulatory subunits (in blue, not individually labeled) as well as three peripheral stalks each consisting of an EG heterodimer. Two of these EG heterodimers are labeled and the top of the third is visible at the back of the complex. The C and H subunits help to attach the V1 subcomplex to Vo serve important regulatory roles. The Vo subcomplex includes a ring of proteolipid subunits (brown) and the a-subunit. The a-subunit is a two-domain protein with a cytoplasmic domain (aNT) and an integral membrane domain (aCT). All figures were constructed using Biorender.com.
FIGURE 2
FIGURE 2
Reversible disassembly of the yeast V-ATPase. Active, assembled V-ATPases (left) couple hydrolysis of ATP to H+ transport across membranes. In yeast, glucose deprivation triggers disassembly and inactivation of some of the V-ATPase complexes. The V1 complex and subunit C are separately released from the membrane-bound Vo subcomplex into the cytosol, and both ATP hydrolysis and H+-transport are inhibited (right). Upon glucose readdition, the RAVE complex helps to catalyze V-ATPase reassembly and reactivation.
FIGURE 3
FIGURE 3
Map of interactions between yeast RAVE subunits and the V-ATPase and structural modeling of Rav1. Regions of interaction between subunits of the RAVE complex and between RAVE and V-ATPase subunits (labeled in Figure 1) are shown (Smardon et al., 2015). Structural models for two regions of Rav1 are also shown. Amino acids 2-672 of Rav1 were modeled on the double propeller of Apaf-1 (apoptotic protease activating factor-1;PDB 5JUY) by the Phyre2 server (Kelley et al., 2015). There is 14% amino acid sequence identity in this region, which was modeled with 100% confidence. In the view shown, the first β-propeller is viewed from the top, while the second β-propeller is viewed from the side. Amino acids 937–1113 of Rav1 were modeled on the α-solenoid region of chain A of gemin-5 (PDB 6RNS). There is 18% amino acid sequence identity with this region of Rav1, and it was modeled to the single highest scoring template with a confidence estimate of 98.7%. Black lines indicate regions exhibiting protein-protein interactions and gray lines indicate regions corresponding to the homology models.
FIGURE 4
FIGURE 4
Order of events in RAVE-driven catalysis of V-ATPase reassembly. Assembled and active V-ATPases (1) are dissociated upon glucose deprivation as described in Figure 2. The RAVE complex binds to cytosolic V1 complexes (2) and this RAVE-V1 complex then binds to subunit C (3). After glucose readdition, RAVE is recruited to Vo complexes at the vacuolar membrane and catalyzes recruitment and functional reassembly of V1 and subunit C with Vo complexes (4). RAVE is then released and able to catalyze another cycle of reassembly.
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