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Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 41749

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Prof. Dr. James Konopka

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Guest Editor

Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY 11794-5222, USA
Interests: molecular mechanisms of fungal pathogenesis; fungal cell signaling; fungal morphogenesis; fungal virulence factors; plasma membrane microdomains

Prof. Dr. Mark Rose

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Guest Editor

1. Department of Biology, Georgetown University, Washington, DC 20057, USA
2. Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
Interests: cell biology in the budding yeast; Saccharomyces cerevisiae; cell and nuclear fusion; regulation of meiosis

Special Issue Information

Dear Colleagues,

Few scientists have made so many seminal contributions to our understanding of transmembrane and intracellular signal transduction mechanisms than Professor Jeremy Thorner. Moreover, few have so artfully exploited the cell biology of the humble of budding yeast to learn so much about how these processes work in all eukaryotic cells, with a broad impact on the mechanisms of disease and the development of novel therapeutic approaches. The scientific world has undergone many changes since 1971, when Jeremy published his first manuscript, but through the years he has steadily been at the forefront of the revolution in basic research studies on many areas of cell signalling.

After earning his PhD from Harvard University in 1972, and a short postdoctoral stint at Stanford, Prof. Thorner began his career as an independent scientist in 1974 as an Assistant Professor at the University of California at Berkeley, where he has remained until retirement in 2020. His early studies on the synthesis and processing of yeast-mating pheromones provided a detailed molecular understanding of how larger proteins could be processed into smaller hormone units and secreted. In the case of alpha factor, his lab showed that it is secreted through the normal secretory pathway, along the way discovering the prototypical eukaryotic prohormone protease, Kex2. In the case of a-factor, the lipopeptide pheromone is secreted through a transmembrane protein pump, identifying a new role for ABC transporters and establishing a paradigm for the role of ABC transporters in antigen presentation. Subsequent studies on the mechanisms of pheromone signalling established many novel mechanisms for the regulation of G-protein coupled receptor signalling and MAP kinase pathways. In particular, his lab elucidated two pathways of negative regulation, identifying the role of the GAP, Sst2, and the regulated endocytosis by the alpha-arrestins. More recently, Prof. Thorner has focused on the mechanisms that regulate lipid signalling and organization, and plasma membrane structure that are critical for cell signalling pathways to function properly. In particular, he has focused on the synthesis and function of phospho-inosotides in regulating several critical pathways.

Prof. Thorner has contributed significantly to the scientific community in many other ways, including serving on numerous grant review panels and on the editorial boards of many scientific journals. He has mentored a large group of successful scientists from his own lab and previously served as a Director of an NIH-sponsored training grant in cellular and molecular biology. In recognition of his achievements, Prof. Thorner has been invited to lecture at conferences around the world and has been elected as a Fellow of several scientific societies, including the American Society for the Advancement Science, the American Academy of Microbiology and the National Academy of Sciences. Given his many contributions, it is fitting that he was recognized with a Lifetime Achievement Award from the Genetics Society of America.

Biomolecules is pleased to host a Special Issue honouring Prof. Jeremy Thorner for his outstanding achievements in basic science and in mentoring an outstanding group of scientists who are continuing to discover novel aspects of cell signalling that will be highlighted in this issue.

Prof. Dr. James Konopka
Prof. Dr. Mark Rose
Guest Editors

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Published Papers (11 papers)

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17 pages, 3938 KiB

Open AccessFeature PaperArticle

Cla4p Kinase Activity Is Down-Regulated by Fus3p during Yeast Mating

by Junwon Kim and Mark D. Rose

Biomolecules 2022, 12(4), 598; https://doi.org/10.3390/biom12040598 - 18 Apr 2022

Cited by 3 | Viewed by 2234

Abstract

In Saccharomyces cerevisiae, the p21-activated kinase Cla4p regulates polarized morphogenesis and cytokinesis. However, it remains unknown how Cla4p kinase activity is regulated. After pheromone exposure, yeast cells temporally separate the mitotic and mating programs by sequestering Fus2p in the nucleus until cell cycle completion, after which Fus2p exits to facilitate cell fusion. Previously, we showed that sequestration is regulated by two opposing protein kinases, Cla4p and Fus3p. Phosphorylation of Fus2p-S67 by Cla4p promotes nuclear localization by both activating nuclear import and blocking export. During mating, phosphorylation of Fus2p-S85 and Fus2p-S100 by Fus3p promotes nuclear export and blocks import. Here, we find that Cla4p kinase activity is itself down-regulated during mating. Pheromone exposure causes Cla4p hyper-phosphorylation and reduced Fus2p-S67 phosphorylation, dependent on Fus3p. Multiple phosphorylation sites in Cla4p are mating- and/or Fus3p-specific. Of these, Cla4p-S186 phosphorylation reduced the kinase activity of Cla4p, in vitro. A phosphomimetic cla4-S186E mutation caused a strong reduction in Fus2p-S67 phosphorylation and nuclear localization, in vivo. More generally, a non-phosphorylatable mutation, cla4-S186A, caused failure to maintain pheromone arrest and delayed formation of the mating-specific septin morphology. Thus, as cells enter the mating pathway, Fus3p counteracts Cla4p kinase activity to allow proper mating differentiation. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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35 pages, 12600 KiB

Open AccessArticle

TORC1 Signaling Controls the Stability and Function of α-Arrestins Aly1 and Aly2

by Ray W. Bowman II, Eric M. Jordahl, Sydnie Davis, Stefanie Hedayati, Hannah Barsouk, Nejla Ozbaki-Yagan, Annette Chiang, Yang Li and Allyson F. O’Donnell

Biomolecules 2022, 12(4), 533; https://doi.org/10.3390/biom12040533 - 31 Mar 2022

Cited by 6 | Viewed by 3212

Abstract

Nutrient supply dictates cell signaling changes, which in turn regulate membrane protein trafficking. To better exploit nutrients, cells relocalize membrane transporters via selective protein trafficking. Key in this reshuffling are the α-arrestins, selective protein trafficking adaptors conserved from yeast to man. α-Arrestins bind membrane proteins, controlling the ubiquitination and endocytosis of many transporters. To prevent the spurious removal of membrane proteins, α-arrestin-mediated endocytosis is kept in check through phospho-inhibition. This phospho-regulation is complex, with up to 87 phospho-sites on a single α-arrestin and many kinases/phosphatases targeting α-arrestins. To better define the signaling pathways controlling paralogous α-arrestins, Aly1 and Aly2, we screened the kinase and phosphatase deletion (KinDel) library, which is an array of all non-essential kinase and phosphatase yeast deletion strains, for modifiers of Aly-mediated phenotypes. We identified many Aly regulators, but focused our studies on the TORC1 kinase, a master regulator of nutrient signaling across eukaryotes. We found that TORC1 and its signaling effectors, the Sit4 protein phosphatase and Npr1 kinase, regulate the phosphorylation and stability of Alys. When Sit4 is lost, Alys are hyperphosphorylated and destabilized in an Npr1-dependent manner. These findings add new dimensions to our understanding of TORC1 regulation of α-arrestins and have important ramifications for cellular metabolism. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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13 pages, 1833 KiB

Open AccessArticle

Pheromone Guidance of Polarity Site Movement in Yeast

by Katherine C. Jacobs and Daniel J. Lew

Biomolecules 2022, 12(4), 502; https://doi.org/10.3390/biom12040502 - 26 Mar 2022

Cited by 2 | Viewed by 2478

Abstract

Cells’ ability to track chemical gradients is integral to many biological phenomena, including fertilization, development, accessing nutrients, and combating infection. Mating of the yeast Saccharomyces cerevisiae provides a tractable model to understand how cells interpret the spatial information in chemical gradients. Mating yeast of the two different mating types secrete distinct peptide pheromones, called a-factor and α-factor, to communicate with potential partners. Spatial gradients of pheromones are decoded to guide mobile polarity sites so that polarity sites in mating partners align towards each other, as a prerequisite for cell-cell fusion and zygote formation. In ascomycetes including S. cerevisiae, one pheromone is prenylated (a-factor) while the other is not (α-factor). The difference in physical properties between the pheromones, combined with associated differences in mechanisms of secretion and extracellular pheromone metabolism, suggested that the pheromones might differ in the spatial information that they convey to potential mating partners. However, as mating appears to be isogamous in this species, it is not clear why any such signaling difference would be advantageous. Here we report assays that directly track movement of the polarity site in each partner as a way to understand the spatial information conveyed by each pheromone. Our findings suggest that both pheromones convey very similar information. We speculate that the different pheromones were advantageous in ancestral species with asymmetric mating systems and may represent an evolutionary vestige in yeasts that mate isogamously. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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26 pages, 2815 KiB

Open AccessEditor’s ChoiceArticle

Multi-Omics Analysis of Multiple Glucose-Sensing Receptor Systems in Yeast

by Shuang Li, Yuanyuan Li, Blake R. Rushing, Sarah E. Harris, Susan L. McRitchie, Daniel Dominguez, Susan J. Sumner and Henrik G. Dohlman

Biomolecules 2022, 12(2), 175; https://doi.org/10.3390/biom12020175 - 21 Jan 2022

Cited by 10 | Viewed by 4016

Abstract

The yeast Saccharomyces cerevisiae has long been used to produce alcohol from glucose and other sugars. While much is known about glucose metabolism, relatively little is known about the receptors and signaling pathways that indicate glucose availability. Here, we compare the two glucose receptor systems in S. cerevisiae. The first is a heterodimer of transporter-like proteins (transceptors), while the second is a seven-transmembrane receptor coupled to a large G protein (Gpa2) that acts in coordination with two small G proteins (Ras1 and Ras2). Through comprehensive measurements of glucose-dependent transcription and metabolism, we demonstrate that the two receptor systems have distinct roles in glucose signaling: the G-protein-coupled receptor directs carbohydrate and energy metabolism, while the transceptors regulate ancillary processes such as ribosome, amino acids, cofactor and vitamin metabolism. The large G-protein transmits the signal from its cognate receptor, while the small G-protein Ras2 (but not Ras1) integrates responses from both receptor pathways. Collectively, our analysis reveals the molecular basis for glucose detection and the earliest events of glucose-dependent signal transduction in yeast. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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22 pages, 9973 KiB

Open AccessArticle

Heterologous Expression and Assembly of Human TLR Signaling Components in Saccharomyces cerevisiae

by Julia María Coronas-Serna, Elba del Val, Jonathan C. Kagan, María Molina and Víctor J. Cid

Biomolecules 2021, 11(11), 1737; https://doi.org/10.3390/biom11111737 - 22 Nov 2021

Cited by 4 | Viewed by 3634

Abstract

Toll-like receptor (TLR) signaling is key to detect pathogens and initiating inflammation. Ligand recognition triggers the assembly of supramolecular organizing centers (SMOCs) consisting of large complexes composed of multiple subunits. Building such signaling hubs relies on Toll Interleukin-1 Receptor (TIR) and Death Domain (DD) protein-protein interaction domains. We have expressed TIR domain-containing components of the human myddosome (TIRAP and MyD88) and triffosome (TRAM and TRIF) SMOCs in Saccharomyces cerevisiae, as a platform for their study. Interactions between the TLR4 TIR domain, TIRAP, and MyD88 were recapitulated in yeast. Human TIRAP decorated the yeast plasma membrane (PM), except for the bud neck, whereas MyD88 was found at cytoplasmic spots, which were consistent with endoplasmic reticulum (ER)-mitochondria junctions, as evidenced by co-localization with Mmm1 and Mdm34, components of the ER and Mitochondria Encounter Structures (ERMES). The formation of MyD88-TIRAP foci at the yeast PM was reinforced by co-expression of a membrane-bound TLR4 TIR domain. Mutations in essential residues of their TIR domains aborted MyD88 recruitment by TIRAP, but their respective subcellular localizations were unaltered. TRAM and TRIF, however, did not co-localize in yeast. TRAM assembled long PM-bound filaments that were disrupted by co-expression of the TLR4 TIR domain. Our results evidence that the yeast model can be exploited to study the interactions and subcellular localization of human SMOC components in vivo. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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26 pages, 6249 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Cdc42-Specific GTPase-Activating Protein Rga1 Squelches Crosstalk between the High-Osmolarity Glycerol (HOG) and Mating Pheromone Response MAPK Pathways

by Jesse C. Patterson, Louise S. Goupil and Jeremy Thorner

Biomolecules 2021, 11(10), 1530; https://doi.org/10.3390/biom11101530 - 17 Oct 2021

Cited by 5 | Viewed by 3873

Abstract

Eukaryotes utilize distinct mitogen/messenger-activated protein kinase (MAPK) pathways to evoke appropriate responses when confronted with different stimuli. In yeast, hyperosmotic stress activates MAPK Hog1, whereas mating pheromones activate MAPK Fus3 (and MAPK Kss1). Because these pathways share several upstream components, including the small guanosine-5'-triphosphate phosphohydrolase (GTPase) cell-division-cycle-42 (Cdc42), mechanisms must exist to prevent inadvertent cross-pathway activation. Hog1 activity is required to prevent crosstalk to Fus3 and Kss1. To identify other factors required to maintain signaling fidelity during hypertonic stress, we devised an unbiased genetic selection for mutants unable to prevent such crosstalk even when active Hog1 is present. We repeatedly isolated truncated alleles of RGA1, a Cdc42-specific GTPase-activating protein (GAP), each lacking its C-terminal catalytic domain, that permit activation of the mating MAPKs under hyperosmotic conditions despite Hog1 being present. We show that Rga1 down-regulates Cdc42 within the high-osmolarity glycerol (HOG) pathway, but not the mating pathway. Because induction of mating pathway output via crosstalk from the HOG pathway takes significantly longer than induction of HOG pathway output, our findings suggest that, under normal conditions, Rga1 contributes to signal insulation by limiting availability of the GTP-bound Cdc42 pool generated by hypertonic stress. Thus, Rga1 action contributes to squelching crosstalk by imposing a type of “kinetic proofreading”. Although Rga1 is a Hog1 substrate in vitro, we eliminated the possibility that its direct Hog1-mediated phosphorylation is necessary for its function in vivo. Instead, we found first that, like its paralog Rga2, Rga1 is subject to inhibitory phosphorylation by the S. cerevisiae cyclin-dependent protein kinase 1 (Cdk1) ortholog Cdc28 and that hyperosmotic shock stimulates its dephosphorylation and thus Rga1 activation. Second, we found that Hog1 promotes Rga1 activation by blocking its Cdk1-mediated phosphorylation, thereby allowing its phosphoprotein phosphatase 2A (PP2A)-mediated dephosphorylation. These findings shed light on why Hog1 activity is required to prevent crosstalk from the HOG pathway to the mating pheromone response pathway. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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15 pages, 2579 KiB

Open AccessArticle

Post-Transcriptional Control of Mating-Type Gene Expression during Gametogenesis in Saccharomyces cerevisiae

by Randi Yeager, G. Guy Bushkin, Emily Singer, Rui Fu, Benjamin Cooperman and Michael McMurray

Biomolecules 2021, 11(8), 1223; https://doi.org/10.3390/biom11081223 - 17 Aug 2021

Cited by 1 | Viewed by 3688

Abstract

Gametogenesis in diploid cells of the budding yeast Saccharomyces cerevisiae produces four haploid meiotic products called spores. Spores are dormant until nutrients trigger germination, when they bud asexually or mate to return to the diploid state. Each sporulating diploid produces a mix of spores of two haploid mating types, a and α. In asexually dividing haploids, the mating types result from distinct, mutually exclusive gene expression programs responsible for production of mating pheromones and the receptors to sense them, all of which are silent in diploids. It was assumed that spores only transcribe haploid- and mating-type-specific genes upon germination. We find that dormant spores of each mating type harbor transcripts representing all these genes, with the exception of Mata1, which we found to be enriched in a spores. Mata1 transcripts, from a rare yeast gene with two introns, were mostly unspliced. If the retained introns reflect tethering to the MATa locus, this could provide a mechanism for biased inheritance. Translation of pheromones and receptors were repressed at least until germination. We find antisense transcripts to many mating genes that may be responsible. These findings add to the growing number of examples of post-transcriptional regulation of gene expression during gametogenesis. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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27 pages, 4159 KiB

Open AccessFeature PaperReview

Comparison of Experimental Approaches Used to Determine the Structure and Function of the Class D G Protein-Coupled Yeast α-Factor Receptor

by Mark E. Dumont and James B. Konopka

Biomolecules 2022, 12(6), 761; https://doi.org/10.3390/biom12060761 - 30 May 2022

Cited by 2 | Viewed by 2299

Abstract

The Saccharomyces cerevisiae α-factor mating pheromone receptor (Ste2p) has been studied as a model for the large medically important family of G protein-coupled receptors. Diverse yeast genetic screens and high-throughput mutagenesis of STE2 identified a large number of loss-of-function, constitutively-active, dominant-negative, and intragenic second-site suppressor mutants as well as mutations that specifically affect pheromone binding. Facile genetic manipulation of Ste2p also aided in targeted biochemical approaches, such as probing the aqueous accessibility of substituted cysteine residues in order to identify the boundaries of the seven transmembrane segments, and the use of cysteine disulfide crosslinking to identify sites of intramolecular contacts in the transmembrane helix bundle of Ste2p and sites of contacts between the monomers in a Ste2p dimer. Recent publication of a series of high-resolution cryo-EM structures of Ste2p in ligand-free, agonist-bound and antagonist-bound states now makes it possible to evaluate the results of these genetic and biochemical strategies, in comparison to three-dimensional structures showing activation-related conformational changes. The results indicate that the genetic and biochemical strategies were generally effective, and provide guidance as to how best to apply these experimental strategies to other proteins. These strategies continue to be useful in defining mechanisms of signal transduction in the context of the available structures and suggest aspects of receptor function beyond what can be discerned from the available structures. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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26 pages, 872 KiB

Open AccessEditor’s ChoiceReview

Kinases on Double Duty: A Review of UniProtKB Annotated Bifunctionality within the Kinome

by Aziz M. Rangwala, Victoria R. Mingione, George Georghiou and Markus A. Seeliger

Biomolecules 2022, 12(5), 685; https://doi.org/10.3390/biom12050685 - 11 May 2022

Cited by 2 | Viewed by 3189

Abstract

Phosphorylation facilitates the regulation of all fundamental biological processes, which has triggered extensive research of protein kinases and their roles in human health and disease. In addition to their phosphotransferase activity, certain kinases have evolved to adopt additional catalytic functions, while others have completely lost all catalytic activity. We searched the Universal Protein Resource Knowledgebase (UniProtKB) database for bifunctional protein kinases and focused on kinases that are critical for bacterial and human cellular homeostasis. These kinases engage in diverse functional roles, ranging from environmental sensing and metabolic regulation to immune-host defense and cell cycle control. Herein, we describe their dual catalytic activities and how they contribute to disease pathogenesis. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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35 pages, 2833 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Coordination of RNA Processing Regulation by Signal Transduction Pathways

by Veronica Ruta, Vittoria Pagliarini and Claudio Sette

Biomolecules 2021, 11(10), 1475; https://doi.org/10.3390/biom11101475 - 7 Oct 2021

Cited by 9 | Viewed by 4231

Abstract

Signal transduction pathways transmit the information received from external and internal cues and generate a response that allows the cell to adapt to changes in the surrounding environment. Signaling pathways trigger rapid responses by changing the activity or localization of existing molecules, as well as long-term responses that require the activation of gene expression programs. All steps involved in the regulation of gene expression, from transcription to processing and utilization of new transcripts, are modulated by multiple signal transduction pathways. This review provides a broad overview of the post-translational regulation of factors involved in RNA processing events by signal transduction pathways, with particular focus on the regulation of pre-mRNA splicing, cleavage and polyadenylation. The effects of several post-translational modifications (i.e., sumoylation, ubiquitination, methylation, acetylation and phosphorylation) on the expression, subcellular localization, stability and affinity for RNA and protein partners of many RNA-binding proteins are highlighted. Moreover, examples of how some of the most common signal transduction pathways can modulate biological processes through changes in RNA processing regulation are illustrated. Lastly, we discuss challenges and opportunities of therapeutic approaches that correct RNA processing defects and target signaling molecules. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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16 pages, 1023 KiB

Open AccessEditor’s ChoiceReview

Stress Relief Techniques: p38 MAPK Determines the Balance of Cell Cycle and Apoptosis Pathways

by Robert H. Whitaker and Jeanette Gowen Cook

Biomolecules 2021, 11(10), 1444; https://doi.org/10.3390/biom11101444 - 2 Oct 2021

Cited by 52 | Viewed by 6759

Abstract

Protein signaling networks are formed from diverse and inter-connected cell signaling pathways converging into webs of function and regulation. These signaling pathways both receive and conduct molecular messages, often by a series of post-translation modifications such as phosphorylation or through protein–protein interactions via intrinsic motifs. The mitogen activated protein kinases (MAPKs) are components of kinase cascades that transmit signals through phosphorylation. There are several MAPK subfamilies, and one subfamily is the stress-activated protein kinases, which in mammals is the p38 family. The p38 enzymes mediate a variety of cellular outcomes including DNA repair, cell survival/cell fate decisions, and cell cycle arrest. The cell cycle is itself a signaling system that precisely controls DNA replication, chromosome segregation, and cellular division. Another indispensable cell function influenced by the p38 stress response is programmed cell death (apoptosis). As the regulators of cell survival, the BCL2 family of proteins and their dynamics are exquisitely sensitive to cell stress. The BCL2 family forms a protein–protein interaction network divided into anti-apoptotic and pro-apoptotic members, and the balance of binding between these two sides determines cell survival. Here, we discuss the intersections among the p38 MAPK, cell cycle, and apoptosis signaling pathways. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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