A metabolic switch on a yeast arrestin connects glucose signaling to transporter endocytosis

Endocytosis is a critical component of plasma membrane dynamics, by allowing the removal of proteins such as transporters or receptors in response to environmental cues. In yeast, transporter endocytosis requires their ubiquitylation at the plasma membrane by the Nedd4-like E3 ubiquitin ligase, Rsp5. Since the ubiquitylation of a given transporter occurs only in response to specific signals, this raises the question of how substrate specificity is achieved, and how it is regulated dynamically. Various "adaptor" proteins were identified, which may promote the interaction between Rsp5 and its substrates, and may provide a basis for this regulation. However, how they modulate Rsp5 function in response to extracellular stimuli is unknown. We addressed this question by studying a model transporter, Jen1, which is a lactate transporter induced in the presence of lactate and endocytosed in response to glucose (Paiva et al., JBC 2009). We identified an Rsp5 adaptor protein that belongs to the alpha-arrestin family, Art4 (also named Rod1), as essential for Jen1 ubiquitylation and endocytosis of in response to glucose. Interestingly, when cells are grown in lactate medium to induce Jen1 expression, Art4 is strongly phosphorylated by the yeast AMPK homologue, Snf1. Addition of glucose, known to trigger Jen1 endocytosis, leads to a rapid dephosphorylation of Art4, a process that requires the PP1 phosphatase regulatory subunit Reg1. This dephosphorylation allows Art4 ubiquitylation by Rsp5, and we provide details on the molecular mechanism of this regulation. We also show that Art4 ubiquitylation is required for Jen1 endocytosis. Therefore, a switch in Art4 post-translational modifications occurs in response to glucose and is required to modulate its function as an adaptor of Rsp5. This establishes yeast arrestin-like proteins as key regulators of transporter endocytosis in response to extracellular signals

Perceptions and practice of personal protective behaviors to prevent COVID-19 transmission in the G7 nations

Introduction: To combat the transmission of COVID-19, countries have endorsed a series of non-pharmaceutical measures. We evaluated the practice and perceptions of personal protective measures and social distancing across the G7 countries. Methods: Data were collected during 19–21 March 2020, from 7005 of Kantar’s online panelists aged >16 years across the G7 countries: Canada, France, Great Britain, Germany, Italy, Japan, and the United States. Data were post-stratified and weighted to match population distributions of the respective countries. Descriptive and multivariable analyses were conducted in late March 2020. Results: Males (vs females) and those less educated (vs college graduates) were less likely to practice personal protective measures and social distancing. Younger adults were also less likely to practice social distancing (vs adults >65 years old). Respondents who expressed concern about the impact of COVID-19 on their health, income or education had higher odds of practicing personal protective measures (AOR=2.81, 1.74, and 1.54, respectively) and social distancing (AOR=3.18, 1.68, and 1.89, respectively) compared to those who did not. Those who perceived precautionary measures as highly effective were also more likely to practice personal protective measures (AOR=2.05) and social distancing (AOR=3.99) compared to those who perceived them as ineffective. Conclusions: Concerns about COVID-19 and perceived effectiveness of precautionary measures strongly predict practice of protective measures, regardless of the types of behaviors. Population-wide interventions should focus on ensuring increased adherence and tailoring communications to groups that are less likely to practice protective behaviors

Public perspective on the governmental response, communication and trust in the governmental decisions in mitigating COVID-19 early in the pandemic across the G7 countries

The COVID-19 pandemic poses a threat to global health and security inciting governments with the responsibility to respond with measures that ensure the health and safety of their communities. We assessed public attitudes towards governmental actions to combat the COVID-19 pandemic in the G7 countries. Data were collected during 19th–21st March 2020, from 7005 Kantar's online panelists aged >16 years across the G7 countries: Canada, France, Great Britain, Germany, Italy, Japan, and the United States. Data were post-stratified and weighted to match population distributions of the respective countries. Descriptive and multivariable analyses were conducted. Amongst the G7, Japan had the lowest level of approval of governmental response to the pandemic, rating governmental communication as good, and trusting governmental decisions (35.0%, 33.6%, and 38.0%, respectively), followed by the U.S. (52.9%, 64.6%, and 59.9%, respectively). Understanding of which measures one can personally take to help limit the spread of the coronavirus was significantly associated with approving governmental response (aOR = 2.88), rating government communication as good (aOR = 2.70) and trust in future governmental decisions (aOR = 2.73). Those who reported government/politicians and friends/family as their most trusted information source were more likely to report approval, higher rating, and/or trust toward governmental actions. Public attitudes towards governmental actions against COVID-19 varied substantially across the G7 countries and were associated with the understanding of measures and source of information that respondents most trusted. Timely and accurate communication is essential to enhance public engagement to control the COVID-19 pandemic

Compartmentation of Redox Metabolism in Malaria Parasites

Malaria, caused by the apicomplexan parasite Plasmodium, still represents a major threat to human health and welfare and leads to about one million human deaths annually. Plasmodium is a rapidly multiplying unicellular organism undergoing a complex developmental cycle in man and mosquito – a life style that requires rapid adaptation to various environments. In order to deal with high fluxes of reactive oxygen species and maintain redox regulatory processes and pathogenicity, Plasmodium depends upon an adequate redox balance. By systematically studying the subcellular localization of the major antioxidant and redox regulatory proteins, we obtained the first complete map of redox compartmentation in Plasmodium falciparum. We demonstrate the targeting of two plasmodial peroxiredoxins and a putative glyoxalase system to the apicoplast, a non-photosynthetic plastid. We furthermore obtained a complete picture of the compartmentation of thioredoxin- and glutaredoxin-like proteins. Notably, for the two major antioxidant redox-enzymes – glutathione reductase and thioredoxin reductase – Plasmodium makes use of alternative-translation-initiation (ATI) to achieve differential targeting. Dual localization of proteins effected by ATI is likely to occur also in other Apicomplexa and might open new avenues for therapeutic intervention

Seipin is required for converting nascent to mature lipid droplets

How proteins control the biogenesis of cellular lipid droplets (LDs) is poorly understood. Using Drosophila and human cells, we show here that seipin, an ER protein implicated in LD biology, mediates a discrete step in LD formation—the conversion of small, nascent LDs to larger, mature LDs. Seipin forms discrete and dynamic foci in the ER that interact with nascent LDs to enable their growth. In the absence of seipin, numerous small, nascent LDs accumulate near the ER and most often fail to grow. Those that do grow prematurely acquire lipid synthesis enzymes and undergo expansion, eventually leading to the giant LDs characteristic of seipin deficiency. Our studies identify a discrete step of LD formation, namely the conversion of nascent LDs to mature LDs, and define a molecular role for seipin in this process, most likely by acting at ER-LD contact sites to enable lipid transfer to nascent LDs. DOI: http://dx.doi.org/10.7554/eLife.16582.00

Endocytic regulation of alkali metal transport proteins in mammals, yeast and plants

The relative concentrations of ions and solutes inside cells are actively maintained by several classes of transport proteins, in many cases against their concentration gradient. These transport processes, which consume a large portion of cellular energy, must be constantly regulated. Many structurally distinct families of channels, carriers, and pumps have been characterized in considerable detail during the past decades and defects in the function of some of these proteins have been linked to a growing list of human diseases. The dynamic regulation of the transport proteins present at the cell surface is vital for both normal cellular function and for the successful adaptation to changing environments. The composition of proteins present at the cell surface is controlled on both the transcriptional and post-translational level. Post-translational regulation involves highly conserved mechanisms of phosphorylation- and ubiquitylation-dependent signal transduction routes used to modify the cohort of receptors and transport proteins present under any given circumstances. In this review, we will summarize what is currently known about one facet of this regulatory process: the endocytic regulation of alkali metal transport proteins. The physiological relevance, major contributors, parallels and missing pieces of the puzzle in mammals, yeast and plants will be discussed.This work was supported by grant BFU2011-30197-C03-03 from the Ministerio de Ciencia e Innovacion (Spain). V.L.-T. is supported by a fellowship from the Universidad Politecnica de Valencia. C. P. is supported by a fellowship from the Consejo Superior de Investigaciones Cientificas (Spain).Mulet Salort, JM.; Llopis Torregrosa, V.; Primo Planta, C.; Marques Romero, MC.; Yenush, L. (2013). 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The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance

The peroxisomal proliferating-activated receptors (PPARs) are lipid-sensing transcription factors that have a role in embryonic development, but are primarily known for modulating energy metabolism, lipid storage, and transport, as well as inflammation and wound healing. Currently, there is no consensus as to the overall combined function of PPARs and why they evolved. We hypothesize that the PPARs had to evolve to integrate lipid storage and burning with the ability to reduce oxidative stress, as energy storage is essential for survival and resistance to injury/infection, but the latter increases oxidative stress and may reduce median survival (functional longevity). In a sense, PPARs may be an evolutionary solution to something we call the 'hypoxia-lipid' conundrum, where the ability to store and burn fat is essential for survival, but is a 'double-edged sword', as fats are potentially highly toxic. Ways in which PPARs may reduce oxidative stress involve modulation of mitochondrial uncoupling protein (UCP) expression (thus reducing reactive oxygen species, ROS), optimising forkhead box class O factor (FOXO) activity (by improving whole body insulin sensitivity) and suppressing NFkB (at the transcriptional level). In light of this, we therefore postulate that inflammation-induced PPAR downregulation engenders many of the signs and symptoms of the metabolic syndrome, which shares many features with the acute phase response (APR) and is the opposite of the phenotype associated with calorie restriction and high FOXO activity. In genetically susceptible individuals (displaying the naturally mildly insulin resistant 'thrifty genotype'), suboptimal PPAR activity may follow an exaggerated but natural adipose tissue-related inflammatory signal induced by excessive calories and reduced physical activity, which normally couples energy storage with the ability to mount an immune response. This is further worsened when pancreatic decompensation occurs, resulting in gluco-oxidative stress and lipotoxicity, increased inflammatory insulin resistance and oxidative stress. Reactivating PPARs may restore a metabolic balance and help to adapt the phenotype to a modern lifestyle