Casein kinase 1 controls the activation threshold of an α-arrestin by multisite phosphorylation of the interdomain hinge

Herrador, Antonio; Livas, Daniela; Soletto, Lucía; Léon, Sébastien; Vincent, Olivier

doi:10.1091/mbc.e14-11-1552

Cited by 23 publications

(27 citation statements)

References 56 publications

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“…Therefore, analysis of CreA stability in creB and creD disruption mutant strains is necessary to understand the mechanism of CCR regulation in filamentous fungi. In yeast, phosphorylation of Art1 and Rim8/Art9 has been proposed to limit their association with the plasma membrane (28,30). Analysis of the subcellular localization of CreB and CreD will also augment our understanding of the target of these proteins.…”

Section: Discussionmentioning

confidence: 99%

Improved α-Amylase Production by Dephosphorylation Mutation of CreD, an Arrestin-Like Protein Required for Glucose-Induced Endocytosis of Maltose Permease and Carbon Catabolite Derepression in Aspergillusoryzae

Tanaka

Hiramoto

Tada

et al. 2017

Appl Environ Microbiol

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Aspergillus oryzae produces copious amount of amylolytic enzymes, and MalP, a major maltose permease, is required for the expression of amylase-encoding genes. The expression of these genes is strongly repressed by carbon catabolite repression (CCR) in the presence of glucose. MalP is transported from the plasma membrane to the vacuole by endocytosis, which requires the homolog of E6-AP carboxyl terminus ubiquitin ligase HulA, an ortholog of yeast Rsp5. In yeast, arrestin-like proteins mediate endocytosis as adaptors of Rsp5 and transporters. In the present study, we examined the involvement of CreD, an arrestin-like protein, in glucoseinduced MalP endocytosis and CCR of amylase-encoding genes. Deletion of creD inhibited the glucose-induced endocytosis of MalP, and CreD showed physical interaction with HulA. Phosphorylation of CreD was detected by Western blotting, and two serine residues were determined as the putative phosphorylation sites. However, the phosphorylation state of the serine residues did not regulate MalP endocytosis and its interaction with HulA. Although ␣-amylase production was significantly repressed by creD deletion, both phosphorylation and dephosphorylation mimics of CreD had a negligible effect on ␣-amylase activity. Interestingly, dephosphorylation of CreD was required for CCR relief of amylase genes that was triggered by disruption of the deubiquitinating enzyme-encoding gene creB. The ␣-amylase activity of the creB mutant was 1.6-fold higher than that of the wild type, and the dephosphorylation mimic of CreD further improved the ␣-amylase activity by 2.6-fold. These results indicate that a combination of the dephosphorylation mutation of CreD and creB disruption increased the production of amylolytic enzymes in A. oryzae. IMPORTANCEIn eukaryotes, glucose induces carbon catabolite repression (CCR) and proteolytic degradation of plasma membrane transporters via endocytosis. Glucoseinduced endocytosis of transporters is mediated by their ubiquitination, and arrestinlike proteins act as adaptors of transporters and ubiquitin ligases. In this study, we showed that CreD, an arrestin-like protein, is involved in glucose-induced endocytosis of maltose permease and carbon catabolite derepression of amylase gene expression in Aspergillus oryzae. Dephosphorylation of CreD was required for CCR relief triggered by the disruption of creB, which encodes a deubiquitinating enzyme; a combination of the phosphorylation-defective mutation of CreD and creB disruption dramatically improved ␣-amylase production. This study shows the dual function of an arrestin-like protein and provides a novel approach for improving the production of amylolytic enzymes in A. oryzae.

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Section: Discussionmentioning

confidence: 99%

Improved α-Amylase Production by Dephosphorylation Mutation of CreD, an Arrestin-Like Protein Required for Glucose-Induced Endocytosis of Maltose Permease and Carbon Catabolite Derepression in Aspergillusoryzae

Tanaka

Hiramoto

Tada

et al. 2017

Appl Environ Microbiol

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“…Alterations in lipid asymmetry and external alkalization may also cause some changes in Rim21 or other proteins of the Rim101 pathway. During preparation of this manuscript, it was reported that the activation threshold of the Rim101 pathway is regulated by phosphorylation of Rim8, a downstream molecule of Rim21 (40). Therefore, it is important that future investigations look at the relationship between Rim8 phosphorylation and how Rim21C associates with and dissociates from the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

The C-terminal Cytosolic Region of Rim21 Senses Alterations in Plasma Membrane Lipid Composition

Nishino¹,

Obara²,

Kihara

2015

Journal of Biological Chemistry

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Yeast responds to alterations in plasma membrane lipid asymmetry and external alkalization via the sensor protein Rim21 in the Rim101 pathway. However, the sensing mechanism used by Rim21 remains unclear. Here, we found that the C-terminal cytosolic domain of Rim21 (Rim21C) fused with GFP was associated with the plasma membrane under normal conditions but dissociated upon alterations in lipid asymmetry or external alkalization. This indicates that Rim21C contains a sensor motif. Rim21C contains multiple clusters of charged residues. Among them, three consecutive Glu residues (EEE motif) were essential for Rim21 function and dissociation of Rim21C from the plasma membrane in response to changes in lipid asymmetry. In contrast, positively charged residues adjacent to the EEE motif were required for Rim21C to associate with the membrane. We therefore propose an "antenna hypothesis," in which Rim21C moves to or from the plasma membrane and functions as the sensing mechanism of Rim21.

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“…Herrador et al . have recently reported that the activity of yeast Rim8 (PalF) is antagonized by CK1‐mediated, Rim21‐dependent phosphorylation (Herrador et al, ). We have shown that PalH is phosphorylated in alkaline pH‐ and PalF‐dependent manner, raising the possibility that the same kinase that is recruited by the activated arrestin phosphorylates the receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Since the pioneering studies revealing the involvement of this pathway in systemic candidiasis (Davis et al, 2000), studies with ascomycetes as diverse as the Saccharomycotina Candida albicans (Nobile et al, 2008) and the Pezizomycotina A. nidulans (Bignell et al, 2005) and A. fumigatus (Bertuzzi et al, 2014) have uncovered its key involvement in the ability of these fungi to infect mammalian hosts. Overwhelming evidence indicates that, in ascomycetes, the pal/RIM pathway ambient pH sensor is a transmembrane protein denoted PalH in A. nidulans and Rim21p in S. cerevisiae (Herranz et al, 2005;Herv as-Aguilar et al, 2007;Galindo et al, 2012;Obara et al, 2012;Herrador et al, 2015). This pH sensor is the most appealing component of the pathway to serve as druggable target, although it would be unsuitable for infections caused by the basidiomycetes, for example, Cryptococcus neoformans, given that although the RIM pathway is involved in its pathogenicity (O'Meara et al, 2010;2013;, PalH/Rim21p (and their associated arrestin, see below) appear to be missing in basidiomycete lineage (Cervantes-Ch avez et al, 2010;Ost et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Unlike b-arrestins, a-arrestins, a subfamily including the fungal clade, characteristically contain docking sites for the Rsp5 ubiquitin ligase (Alvarez, 2008) and indeed many of them act as adaptors targeting integral membrane protein partners for ubiquitin-mediated endocytic down-regulation (Lin et al, 2008;Nikko and Pelham, 2009;Karachaliou et al, 2013). In marked contrast, the a-arrestin PalF/Rim8p engaging the PalH/Rim21p receptor acts positively, apparently by mediating its own requisite ubiquitination (Herrador et al, 2009;Herrador et al, 2015). PalF is necessary and, if artificially ubiquitinated, sufficient for the alkaline pH-dependent activation of the pal pathway (Herv as- Galindo et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Mutational analysis of the Aspergillus ambient pH receptor PalH underscores its potential as a target for antifungal compounds

Lucena‐Agell

Hervás-Aguilar

Múnera-Huertas

et al. 2016

Molecular Microbiology

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SummaryThe pal/RIM ambient pH signalling pathway is crucial for the ability of pathogenic fungi to infect hosts. The Aspergillus nidulans 7‐TMD receptor PalH senses alkaline pH, subsequently facilitating ubiquitination of the arrestin PalF. Ubiquitinated PalF triggers downstream signalling events. The mechanism(s) by which PalH transduces the alkaline pH signal to PalF is poorly understood. We show that PalH is phosphorylated in a signal dependent manner, resembling mammalian GPCRs, although PalH phosphorylation, in contrast to mammalian GPCRs, is arrestin dependent. A genetic screen revealed that an ambient‐exposed region comprising the extracellular loop connecting TM4‐TM5 and ambient‐proximal residues within TM5 is required for signalling. In contrast, substitution by alanines of four aromatic residues within TM6 and TM7 results in a weak ‘constitutive’ activation of the pathway. Our data support the hypothesis that PalH mechanistically resembles mammalian GPCRs that signal via arrestins, such that the relative positions of individual helices within the heptahelical bundle determines the Pro316‐dependent transition between inactive and active PalH conformations, governed by an ambient‐exposed region including critical Tyr259 that potentially represents an agonist binding site. These findings open the possibility of screening for agonist compounds stabilizing the inactive conformation of PalH, which might act as antifungal drugs against ascomycetes.

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Casein kinase 1 controls the activation threshold of an α-arrestin by multisite phosphorylation of the interdomain hinge

Cited by 23 publications

References 56 publications

Improved α-Amylase Production by Dephosphorylation Mutation of CreD, an Arrestin-Like Protein Required for Glucose-Induced Endocytosis of Maltose Permease and Carbon Catabolite Derepression in Aspergillusoryzae

Improved α-Amylase Production by Dephosphorylation Mutation of CreD, an Arrestin-Like Protein Required for Glucose-Induced Endocytosis of Maltose Permease and Carbon Catabolite Derepression in Aspergillusoryzae

The C-terminal Cytosolic Region of Rim21 Senses Alterations in Plasma Membrane Lipid Composition

Mutational analysis of the Aspergillus ambient pH receptor PalH underscores its potential as a target for antifungal compounds

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