Rsp5-dependent endocytosis and degradation of the arsenite transporter Acr3 requires its N-terminal acidic tail as an endocytic sorting signal and arrestin-related ubiquitin-ligase adaptors

Wawrzycka, Donata; Sadlak, Joanna; Maciaszczyk-Dziubińska, Ewa; Wysocki, Robert

doi:10.1016/j.bbamem.2019.02.004

Cited by 20 publications

(12 citation statements)

References 70 publications

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“…Our finding that the cytosolic Loop1-2 plays a role in Ypq1’s recognition is consistent with reports on the interaction between Ssh4 and its cargoes at cytosolic regions close to the membrane ( Ma and Burd, 2019 ; Sardana et al, 2019 ). Cytosolic interactions have also been robustly studied for other Rsp5 adaptors and their cargo ( Crapeau et al, 2014 ; Gournas et al, 2016 , 2017 ; Guiney et al, 2016 ; Keener and Babst, 2013 ; Sullivan et al, 2007 ; Wawrzycka et al, 2019 ). However, the prevalence of TM5 or TM7 mutations in our screen (i.e., 44 out of 66 VM-localized mutants) suggested that transmembrane interactions could also be playing an essential role in Ypq1 recognition.…”

Section: Resultsmentioning

confidence: 99%

“…As the cell responds to rapidly changing environments and diverse cellular cues, the membrane protein landscape needs to be constantly remodeled to achieve homeostasis. For example, the protein levels of many yeast plasma membrane (PM) transporters are regulated by their substrate concentrations ( Crapeau et al, 2014 ; Gournas et al, 2010 , 2017 ; Guiney et al, 2016 ; Keener and Babst, 2013 ; Lin et al, 2008 ; Talaia et al, 2017 ; Wawrzycka et al, 2019 ). Low substrate levels, such as low methionine and uracil, stabilize their corresponding PM transporters, Mup1 and Fur4, respectively.…”

Section: Introductionmentioning

confidence: 99%

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A selective transmembrane recognition mechanism by a membrane-anchored ubiquitin ligase adaptor

Arines

Hamlin

Yang

et al. 2020

Journal of Cell Biology

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While it is well-known that E3 ubiquitin ligases can selectively ubiquitinate membrane proteins in response to specific environmental cues, the underlying mechanisms for the selectivity are poorly understood. In particular, the role of transmembrane regions, if any, in target recognition remains an open question. Here, we describe how Ssh4, a yeast E3 ligase adaptor, recognizes the PQ-loop lysine transporter Ypq1 only after lysine starvation. We show evidence of an interaction between two transmembrane helices of Ypq1 (TM5 and TM7) and the single transmembrane helix of Ssh4. This interaction is regulated by the conserved PQ motif. Strikingly, recent structural studies of the PQ-loop family have suggested that TM5 and TM7 undergo major conformational changes during substrate transport, implying that transport-associated conformational changes may determine the selectivity. These findings thus provide critical information concerning the regulatory mechanism through which transmembrane domains can be specifically recognized in response to changing environmental conditions.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A selective transmembrane recognition mechanism by a membrane-anchored ubiquitin ligase adaptor

Arines

Hamlin

Yang

et al. 2020

Journal of Cell Biology

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“…At the plasma membrane, Art3 localises to endocytic sites [Boeke et al., 2014]. This may explain its involvement in the endocytosis of many cargoes [Hatakeyama et al., 2010; O'Donnell et al., 2010, 2013; Crapeau et al., 2014; Prosser et al., 2015; Wawrzycka et al., 2019; Nishimura et al., 2020; Sen et al., 2020]. Consistently, Art3 interacts with subunits of clathrin adaptors of both the plasma‐membrane (AP‐2) or the TGN (AP‐1) [O'Donnell et al., 2010].…”

Section: Localisation Of Art–rsp5 Complexesmentioning

confidence: 99%

“…Further studies described the importance of acidic residues in cargo proteins for their ART‐mediated ubiquitination. The arsenite transporter Acr3 requires an N‐terminal acidic tail for its Art3/Art4‐dependent endocytosis [Wawrzycka et al., 2019]. An acidic patch located in the C‐terminal tail of Jen1 triggers its down‐regulation upon activation of glucose signalling through recruitment of Art4 [Fujita et al., 2018].…”

Section: Principles Of Substrate Recognition By Art–rsp5 Complexesmentioning

confidence: 99%

The α‐arrestin family of ubiquitin ligase adaptors links metabolism with selective endocytosis

Kahlhofer¹,

Léon

Teis³

et al. 2021

Biology of the Cell

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The regulation of nutrient uptake into cells is important, as it allows to either increase biomass for cell growth or to preserve homoeostasis. A key strategy to adjust cellular nutrient uptake is the reconfiguration of the nutrient transporter repertoire at the plasma membrane by the addition of nutrient transporters through the secretory pathway and by their endocytic removal. In this review, we focus on the mechanisms that regulate selective nutrient transporter endocytosis, which is mediated by the α‐arrestin protein family. In the budding yeast Saccharomyces cerevisiae, 14 different α‐arrestins (also named arrestin‐related trafficking adaptors, ARTs) function as adaptors for the ubiquitin ligase Rsp5. They instruct Rsp5 to ubiquitinate subsets of nutrient transporters to orchestrate their endocytosis. The ART proteins are under multilevel control of the major nutrient sensing systems, including amino acid sensing by the general amino acid control and target of rapamycin pathways, and energy sensing by 5′‐adenosine‐monophosphate‐dependent kinase. The function of the six human α‐arrestins is comparably under‐characterised. Here, we summarise the current knowledge about the function, regulation and substrates of yeast ARTs and human α‐arrestins, and highlight emerging communalities and general principles.

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“…Here we add new players in regulating GPI and inositol balance in cells; We show that the paralogous a rrestin-like y east proteins 1 and 2 (Aly1 and Aly2) act as endocytic adaptors for Git1. This is a novel membrane protein cargo for these α-arrestins, which have previously been demonstrated to regulate the trafficking of Gap1, Dip5 and Put4, three amino acid permeases, the G-protein coupled receptor, Ste3, an arsenite transporter, Arr3 (also known as Acr3), and the P-type ATPase involved in salt and lithium homeostasis, Ena1 (Hatakeyama et al ., 2010; O’Donnell et al ., 2010; O’Donnell et al ., 2013; Crapeau et al ., 2014; Hager et al ., 2018; Wawrzycka et al ., 2019; Nishimura et al ., 2020; Sen et al ., 2020). Though only a few transporters are clearly linked to Aly1 and Aly2 to date, the diversity of transmembrane proteins regulated by this family of trafficking adaptor and the signaling cues that dictate their function is rapidly expanding.…”

Section: Introductionmentioning

confidence: 99%

Alpha-arrestins Aly1 and Aly2 regulate trafficking of the glycerophosphoinositol transporter Git1 and impact phospholipid homeostasis

Robinson

Hawbaker

Chiang

et al. 2021

Preprint

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Phosphatidylinositol (PI) is an essential phospholipid and critical component of membrane bilayers. The complete deacylation of PI by phospholipases of the B-type leads to the production of intracellular and extracellular glycerophosphoinositol (GPI), a water-soluble glycerophosphodiester. Extracellular GPI is transported into the cell via Git1, a member of the Major Facilitator Superfamily of transporters that resides at the plasma membrane in yeast. Once internalized, GPI can be degraded to produce inositol, phosphate and glycerol, thereby contributing to reserves of these building blocks. Not surprisingly, GIT1 gene expression is controlled by nutrient balance, with limitation for phosphate or inositol each increasing GIT1 expression to facilitate GPI uptake. Less is known about how Git1 protein levels or localization are controlled. Here we show that the α-arrestins, an important class of protein trafficking adaptor, regulate the localization of Git1 in a manner dependent upon their association with the ubiquitin ligase Rsp5. Specifically, α-arrestin Aly2 is needed for effective Git1 internalization from the plasma membrane under basal conditions. However, in response to GPI-treatment of cells, either Aly1 or Aly2 can promote Git1 trafficking to the vacuole. Retention of Git1 at the cell surface, as occurs in aly1∆ aly2∆ cells, results in impaired growth in the presences of excess exogenous GPI and results in increased uptake of radiolabeled GPI, suggesting that accumulation of this metabolite or its downstream products leads to cellular toxicity. We further show that regulation of α-arrestin Aly1 by the protein phosphatase calcineurin improves both steady-state and ligand-induced trafficking of Git1 when a mutant allele of Aly1 that mimics the dephosphorylated state at calcineurin-regulated residues is employed. Thus, calcineurin regulation of Aly1 is important for the GPI-ligand induced trafficking of Git1 by this α-arrestin, however, the role of calcineurin in regulating Git1 trafficking is much broader than can simply be explained by regulation of the α-arrestins. Finally, we find that loss of Aly1 and Aly2 leads to an increase in phosphatidylinositol-3-phosphate on the limiting membrane of the vacuole and this alteration is further exacerbated by addition of GPI, suggesting that the effect is at least partially linked to Git1 function. Indeed, loss of Aly1 and Aly2 leads to increased incorporation of inositol label from 3H-inositol-labelled GPI into PI, confirming that internalized GPI influences PI synthesis and indicating a role for the α-arrestins in regulating the process.

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Rsp5-dependent endocytosis and degradation of the arsenite transporter Acr3 requires its N-terminal acidic tail as an endocytic sorting signal and arrestin-related ubiquitin-ligase adaptors

Cited by 20 publications

References 70 publications

A selective transmembrane recognition mechanism by a membrane-anchored ubiquitin ligase adaptor

A selective transmembrane recognition mechanism by a membrane-anchored ubiquitin ligase adaptor

The α‐arrestin family of ubiquitin ligase adaptors links metabolism with selective endocytosis

Alpha-arrestins Aly1 and Aly2 regulate trafficking of the glycerophosphoinositol transporter Git1 and impact phospholipid homeostasis

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