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Review
. 2022 Aug 25;23(17):9615.
doi: 10.3390/ijms23179615.

Insight into the Mammalian Aquaporin Interactome

Susanna Törnroth-Horsefield  1 , Clara Chivasso  2 , Helin Strandberg  1 , Claudia D'Agostino  2 , Carla V T O'Neale  3 , Kevin L Schey  3 , Christine Delporte  2
Affiliations
Review

Insight into the Mammalian Aquaporin Interactome

Susanna Törnroth-Horsefield et al. Int J Mol Sci. .

Abstract

Aquaporins (AQPs) are a family of transmembrane water channels expressed in all living organisms. AQPs facilitate osmotically driven water flux across biological membranes and, in some cases, the movement of small molecules (such as glycerol, urea, CO2, NH3, H2O2). Protein-protein interactions play essential roles in protein regulation and function. This review provides a comprehensive overview of the current knowledge of the AQP interactomes and addresses the molecular basis and functional significance of these protein-protein interactions in health and diseases. Targeting AQP interactomes may offer new therapeutic avenues as targeting individual AQPs remains challenging despite intense efforts.

Keywords: aquaporin; function; interactome; mammalian; protein–protein interaction; trafficking.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 5
Figure 5
Role of the protein–protein interaction involving AQP3. (A) Role in keratinocyte differentiation. Upon glycerol entry through AQP3, glycerol is converted into PG by PLD2. PGly promotes growth arrest and differentiation of keratinocytes. (B) Role in adipocytes. PLIN1 interacts with AQP3 and AQP7 under feeding state. In fasting state, hormones, such as catecholamines, activate the ß-adrenergic receptor, which leads to a subsequent rise in cAMP and activation of PKA. PKA activates HSL hormone-sensitive lipase and thereby stimulates TAG degradation and Gly release. PKA also phosphorylates AQP7, which decreases it affinity for PLIN1 and enables its translocation to the plasma membrane. The AQP3–PLIN1 interaction is reduced by an unknow mechanism and leads to the translocation of AQP3 to the plasma membrane. AQP3 and AQP9 may only play a role in mouse 3T3-L1 adipocytes [101], but not in human or mouse white adipose tissue [109]. cAMP: cyclic adenosine monophosphate; Chol: choline; Glyc: glycerol; Gs: protein Gs; HSL: hormone-sensitive lipase; LIN-7: protein LIN-7 homolog; PC: phosphatidylcholine; PG: phosphatidylglycerol; PKA: protein kinase A; PLIN1: perilipin-1; PLD2: phospholipase D2; TAG: triacylglycerol.
Figure 1
Figure 1
Structural features of mammalian AQPs. (A) Schematic representation of the mammalian AQP topology. Each monomer comprises six transmembrane helices (I–IV) connected by five loops (A–E). Loops B and E fold back into the membrane, forming two half-membrane spanning helices (highlighted in yellow) that harbor the two asparagine–proline–alanine (NPA) motifs. The N- and C-termini are located in the cytoplasm, with the C-terminus typically forming a short amphipathic helix (highlighted in blue) that is a common protein–protein interaction site. (B) Crystal structure of the AQP5 tetramer viewed from the cytoplasmic side (PDB code 3D9S), showing the four individual water channels formed by the monomers with water molecules drawn as red spheres. The central channel through the middle of the tetramer is indicated with an X. (C) Crystal structure of the AQP5-tetramer viewed from the side of the membrane. The loop B and E half-membrane spanning helices and the C-terminal helix are colored yellow and blue, respectively. (D) Zoom-in on the water-conducting channel where water molecules line up in a single file. Residues in the aromatic–arginine (ar/R) and asparagine–proline–alanine (NPA) regions are shown in stick representation. The two half-membrane spanning helices are colored yellow.
Figure 2
Figure 2
Roles of the protein–protein interactions involving AQP0. In the developing lens fiber cell, AQP0 and Cxs join to modulate cell–cell adhesion. AQP0 interacts with ezrin to directly link the plasma membrane with the actin cytoskeleton. Lens-specific beaded intermediate filaments, BFSP1 and BFSP2, also interact with AQP0 to link the plasma membrane to cytoskeletal structures. BSFP1 fragments can reduce AQP0 water permeability. AQP0 interacts with CaM to regulate water permeability. Interactions with AKAP2 modulate AQP0 phosphorylation, which affects CaM binding and water permeability. Interactions with abundant crystallin proteins occur, but with unknown functional consequences. AKAP2: A-kinase anchoring protein 2; BFSP1: beaded filament structural protein 1 (also called filensin); BFSP2: beaded filament structural protein 2 (also called 49 kDa Cytoskeletal Protein (CP49) or phakinin); CaM: calmodulin; Cxs: connexins; PKA: protein kinase A.
Figure 3
Figure 3
Role of the protein–protein interactions involving AQP1. (A) Role in cell migration. During cell migration, increased ion transport at the leading edge of the cells raises intracellular osmolarity that subsequently drives water entry through AQP1. AQP1 binding to FAK, LIN-7 and ß-catenin promotes actin polymerization, at least partly by inhibiting LIN-7 and ß-catenin degradation through the proteasome. (B) Role in APP accumulation in Alzheimer’s disease. AQP1 interaction with APP reduces the binding of BACE1 to APP and inhibits the release of Aß. In addition, the N-terminus of APP released by γ-secretase induces epigenetic modification, leading to increased AQP1 expression. Aß: amyloid-ß peptide; APP: amyloid precursor protein; BACE1: ß-secretase; FAK: Focal-adhesion kinase; LIN-7: protein LIN-7 homolog.
Figure 4
Figure 4
Role of the protein–protein interaction involving AQP2 in kidney collecting duct cells. Upon AVP stimulation, leading to subsequent cAMP increase and PKA activation, AQP2 moves to the plasma membrane thanks to the help of various protein partners. In the absence of hormonal stimulation, AQP2 endocytosis also requires many protein partners. Due to the high number of proteins that bind to AQP2, only some of them are indicated in this figure. 14-3-3: protein 14-3-3-; AC: adenylyl cyclase; AKAP: A-kinase-anchoring protein; AVP: arginine vasopressin; cAMP: cyclic adenosine monophosphate; ERM: ezrin/radixin/moesin protein family; Gs: protein Gs; HSC70: heat shock protein 71 kDa protein; LIP5: lysosomal trafficking regulator-interacting protein 5; MAL: myelin and lymphocyte-associated protein; NEDD4: E3 ubiquitin protein ligase NEDD4; PKA: protein kinase A; PKC: protein kinase C; RhoA: small GTP-Binding Protein RhoA; SAP97: synapse-associated protein 97; Sipa1l1: signal-induced proliferation-associated 1 like 1; SPA1: signal-induced proliferation-associated gene-1; SK3: small-conductance potassium channel; TRPV4: Transient Receptor Potential Cation Channel Subfamily V Member 4: USP4: ubiquitin-specific peptidase 4.
Figure 6
Figure 6
Role of the protein–protein interaction involving AQP4 in astrocytes. The AQP4–TRPV4 interaction plays a role in AQP4 trafficking for calcium entry via TRPV4 binding to CaM. CaM binding, reinforced by AQP4 phosphorylation by PKA, enables AQP4 to move to the plasma membrane. In the plasma membrane, AQP4 also interacts with SUR1, TRPM4, Kir4.1, and DGC. AQP4 also binds to MOR, GLT1, AP, Kir4.1 and Na,K ATPase. CKII can phosphorylate AQP4 to promote its lysosomal targeting and degradation. These protein–protein interactions are likely playing a role in cell volume regulation and cytoskeleton dynamics. AP: clathrin assembly protein complex; CaM: calmodulin; CKII: casein kinase II; DGC: dystrophin-glycoprotein complex; GLT1: glutamate transporter 1; Gs: protein Gs; Kir4.1: inwardly rectifying potassium channel Kir4.1; mGluR5: metabotropic glutamate receptor 5; MOR: mu opioid receptor; Na,K ATPase: sodium, potassium ATPase pump; PKA: protein kinase A; PKC: protein kinase C; SUR1: Sulfonylurea receptor 1; TM2: transmembrane domain 2; TRPM4: Transient Receptor Potential Cation Channel Subfamily M Member 4; TRPV4: Transient Receptor Potential Cation Channel Subfamily V Member 4; µAP 2/3: clathrin assembly protein complexes 2 and 3 µ subunit.
Figure 7
Figure 7
Role of the protein–protein interaction involving AQP5 in salivary gland epithelial cells. Nervous stimulation induces the release of both NA and Ach, which bind to AR and MR. AR activation induces the subsequent activation of Gs protein and AC. AC induces an increase in intracellular levels of cAMP, which activates PKA. MR activation induces the subsequent activation of protein Gq and PLC. PLC cleaves PIP2 into IP3 and DAG. IP3 stimulates calcium release from endoplasmic reticulum and the activation of PKC. These stimuli induce AQP5 trafficking to the plasma membrane. The interaction between AQP5 and NKCC1, AE2 and TRPV4 is likely involved in cell volume regulation and cytoskeleton dynamic regulation, while the interaction between AQP5 and PIP and EZR is likely involved in AQP5 trafficking to the apical plasma membrane. AC: adenylyl cyclase; Ach: acetylcholine; AE2: anion exchanger 2; ß1AR: β1 adrenergic receptors; cAMP: cyclic adenosine monophosphate; DAG: diacylglycerol; EZR: ezrin; Gq: protein Gq; Gs: protein Gs; H: hormone; IP3: inositol 1,4,5 triphosphate; MR: M1 and M3 subtypes of muscarinic receptors; NA: noradrenaline; NKCC1: Na-K-Cl cotransporter 1; PIP: prolactin-inducible protein; PIP2: phosphatidylinositol 4,5-bisphosphate; PLC: phospholipase C; PKA: protein kinase A; PKC: protein kinase C; TRPV4: Transient Receptor Potential Cation Channel Subfamily V Member 4.
Figure 8
Figure 8
Role of the protein–protein interaction involving AQP9. (A) Role in the astrocyte-to-neuron lactate shuttle. Glu enters astrocytes and neurons via GLUT and is transformed into Pyr. In astrocytes, Pyr either used by the mitochondria to produce ATP or is converted to lactate which exits the astrocytes through MCTs 1 and 4. Then, lactate enters neurons via MCT2 and is converted into Pyr, which is used to produce ATP in the mitochondria. Lactate may also directly pass through AQP9. (B) Role in vas deferens cells. Upon adrenergic stimulation, ß2AR is activated and leads to subsequent PKA activation, which in turn phosphorylates CFTR. CTRF–AQP9, CTRF–NHERF1 and NHERF1–AQP9 are likely involved in cell volume control. In addition, the NHERF1–Ezrin interaction is likely coupling cell volume control to cytoskeleton dynamics. AC: adenylyl cyclase; ß2AR: ß2 adrenergic receptor; CFTR: cystic fibrosis transmembrane conductance regulator; Glu: glucose; GLUT: glucose transporter; Gs: protein Gs; H: hormone; MCT: monocarboxylate transporters; NHERF1: Na+/H+ Exchanger Regulatory Factor; PKA: protein kinase A; Pyr: pyruvate.
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