Tricia R Serio
- Professor, Molecular and Cellular Biology
- Professor, Chemistry and Biochemistry
- Professor, BIO5 Institute
- Professor, Genetics - GIDP
Professor Serio received her B.S. in Molecular Biology from Lehigh University in 1991 and completed her graduate work in Molecular Biochemistry and Biophysics as a fellow of the Howard Hughes Medical Institute at Yale University (M.Phil 1995, Ph.D. 1997). From 1997 through 2002, she was a post-doctoral fellow of the Damon Runyon-Walter Winchell Cancer Research Fund at the University of Chicago and a recipient of the Howard Temin Award from the National Cancer Institute at Yale University. She joined the faculty at Brown University as an assistant professor in 2002 where she was named a Pew Scholar in the Biomedical Sciences (2003-2007). In 2008, she was promoted to Associate Professor. In 2012, she moved to the University of Arizona as Professor and Department Head in Molecular and Cellular Biology. Her research focuses on self-perpetuating protein conformations in the yeast Saccharomyces cerevisiae as model for severe neurodegenerative diseases in mammals.
- Ph.D. Molecular Biophysics and Biochemistry
- Yale University, New Haven, Connecticut
- Regulation of Late Gene Expression in Epstein-Barr Virus
- M.Phil. Molecular Biophysics and Biochemistry
- Yale University, New Haven, Connecticut
- B.S. Molecular Biology
- Lehigh University, Bethlehem, Pennsylvania
- Professor and Department Head, University of Arizona, Tucson, Arizona (2012 - Ongoing)
- Associate Professor, Brown University, Providence, Rhode Island (2008 - 2012)
- Assistant Professor, Brown University, Providence, Rhode Island (2002 - 2008)
- Associate Research Scientist, Yale University, New Haven, Connecticut (2001 - 2002)
- Phi Eta Sigma
- Lehigh Univeristy, Spring 1998
- Postdoctoral Fellow
- Damon Runyon-Walter Winchell Cancer Research Rund, Fall 1997
- Predoctoral Fellow
- HHMI, Fall 1991
- Bachelor of Science, Highest Honors, Departmental Honors
- Lehigh University, Spring 1991
- Undergraduate Research Fellow
- HHMI, Lehigh University, Summer 1990
- Phi Beta Kappa
- Lehigh University, Spring 1990
- Mid-career Award for Research Excellence
- American Society for Cell Biology, Fall 2016
- Tucson Public Voices Fellow
- OpEd Project, Fall 2015
- Dean's Award for Excellence in Graduate and Postdoctoral Teaching and Mentoring in the Biological Sciences
- Brown University, Spring 2010
- Scholar in the Biomedical Sciences
- Pew Charitable Trusts, Spring 2003
- Howard Temin Award
- National Cancer Institute, Fall 2001
- Special Fellow
- Leukemia and Lymphoma Society, Spring 2001
Scientific Communciation, Responsible Conduct in Research, Multidisciplinary Approaches to Biological Problem Solving
Cellular Regulation of Protein Misfolding
DissertationMCB 920 (Fall 2016)
Lab Presentations & DiscussionMCB 696A (Fall 2016)
Scientific CommunicationMCB 575 (Fall 2016)
Independent StudyMCB 599 (Summer I 2016)
Independent StudyMCB 699 (Summer I 2016)
DissertationMCB 920 (Spring 2016)
Independent StudyMCB 599 (Spring 2016)
Lab Presentations & DiscussionMCB 696A (Spring 2016)
Directed RsrchMCB 492 (Fall 2015)
DissertationMCB 920 (Fall 2015)
Independent StudyMCB 599 (Fall 2015)
Introduction to ResearchMCB 795A (Fall 2015)
Lab Presentations & DiscussionMCB 696A (Fall 2015)
Scientific CommunicationMCB 575 (Fall 2015)
Directed RsrchMCB 392 (Summer I 2015)
Independent StudyMCB 699 (Summer I 2015)
DissertationMCB 920 (Spring 2015)
Introduction to ResearchMCB 795A (Spring 2015)
Lab Presentations & DiscussionMCB 696A (Spring 2015)
ResearchMCB 900 (Spring 2015)
Science,Society + EthicsCMM 695E (Spring 2015)
Science,Society + EthicsMCB 695E (Spring 2015)
Topic Molec BiologyMCB 595A (Spring 2015)
DissertationMCB 920 (Fall 2014)
Introduction to ResearchMCB 795A (Fall 2014)
Lab Presentations & DiscussionMCB 696A (Fall 2014)
ResearchMCB 900 (Fall 2014)
Scientific CommunicationMCB 575 (Fall 2014)
Directed ResearchNSCS 392 (Spring 2014)
DissertationMCB 920 (Spring 2014)
Introduction to ResearchMCB 795A (Spring 2014)
Lab Presentations & DiscussionMCB 696A (Spring 2014)
ResearchMCB 900 (Spring 2014)
Science,Society + EthicsGENE 695E (Spring 2014)
Science,Society + EthicsMCB 695E (Spring 2014)
Science,Society + EthicsNRSC 695E (Spring 2014)
DissertationMCB 920 (Fall 2013)
Introduction to ResearchMCB 795A (Fall 2013)
Lab Presentations & DiscussionMCB 696A (Fall 2013)
ResearchMCB 900 (Fall 2013)
Scientific CommunicationMCB 575 (Fall 2013)
- Serio, T. R. (2017). Susan Lindquist (1949-2016). Nature chemical biology, 13(2), 127.
- Langlois, C. R., Pei, F., Sindi, S. S., & Serio, T. R. (2016). Distinct Prion Domain Sequences Ensure Efficient Amyloid Propagation by Promoting Chaperone Binding or Processing In Vivo. PLoS genetics, 12(11), e1006417.More infoPrions are a group of proteins that can adopt a spectrum of metastable conformations in vivo. These alternative states change protein function and are self-replicating and transmissible, creating protein-based elements of inheritance and infectivity. Prion conformational flexibility is encoded in the amino acid composition and sequence of the protein, which dictate its ability not only to form an ordered aggregate known as amyloid but also to maintain and transmit this structure in vivo. But, while we can effectively predict amyloid propensity in vitro, the mechanism by which sequence elements promote prion propagation in vivo remains unclear. In yeast, propagation of the [PSI+] prion, the amyloid form of the Sup35 protein, has been linked to an oligopeptide repeat region of the protein. Here, we demonstrate that this region is composed of separable functional elements, the repeats themselves and a repeat proximal region, which are both required for efficient prion propagation. Changes in the numbers of these elements do not alter the physical properties of Sup35 amyloid, but their presence promotes amyloid fragmentation, and therefore maintenance, by molecular chaperones. Rather than acting redundantly, our observations suggest that these sequence elements make complementary contributions to prion propagation, with the repeat proximal region promoting chaperone binding to and the repeats promoting chaperone processing of Sup35 amyloid.
- Serio, T. R. (2016). Think differently. Molecular biology of the cell, 27(21), 3192-3193.More infoAsked to reflect on my own research and career after being selected for the great honor of the Women in Cell Biology Mid-Career Award for Excellence in Research, I found myself contemplating not only how I approach my own science but also how this approach contributes to the larger scientific enterprise. Here I discuss my motivations and their impact on how I conduct my research as one example of the myriad ways to be a scientist. I invite you to consciously consider how, as scientists, we view one another's unique approaches and argue for the importance of diversity of perspective in scientific progress.
- Klaips, C. L., Hochstrasser, M. L., Langlois, C. R., & Serio, T. R. (2015). Correction: Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing. eLife, 4, e06494.
- Brodsky, J. L., Merz, A., & Serio, T. (2014). Organelle and proteome quality control mechanisms: how cells are able to keep calm and carry on. Molecular biology of the cell, 25(6), 733-4.
- Holmes, W. M., Klaips, C. L., & Serio, T. R. (2014). Defining the limits: Protein aggregation and toxicity in vivo. Critical reviews in biochemistry and molecular biology, 49(4), 294-303.More infoAbstract others complementary, to resolve mis-folded proteins when they arise, ranging from refolding through the action of molecular chaperones to elimination through regulated proteolytic mechanisms. These protein quality control pathways are sufficient, under normal conditions, to maintain a functioning proteome, but in response to diverse environmental, genetic and/or stochastic events, protein mis-folding exceeds the corrective capacity of these pathways, leading to the accumulation of aggregates and ultimately toxicity. Particularly devastating examples of these effects include certain neurodegenerative diseases, such as Huntington's Disease, which are associated with the expansion of polyglutamine tracks in proteins. In these cases, protein mis-folding and aggregation are clear contributors to pathogenesis, but uncovering the precise mechanistic links between the two events remains an area of active research. Studies in the yeast Saccharomyces cerevisiae and other model systems have uncovered previously unanticipated complexity in aggregation pathways, the contributions of protein quality control processes to them and the cellular perturbations that result from them. Together these studies suggest that aggregate interactions and localization, rather than their size, are the crucial considerations in understanding the molecular basis of toxicity.
- Holmes, W. M., Mannakee, B. K., Gutenkunst, R. N., & Serio, T. R. (2014). Loss of amino-terminal acetylation suppresses a prion phenotype by modulating global protein folding. Nature communications, 5, 4383.More infoAmino-terminal acetylation is among the most ubiquitous of protein modifications in eukaryotes. Although loss of N-terminal acetylation is associated with many abnormalities, the molecular basis of these effects is known for only a few cases, where acetylation of single factors has been linked to binding avidity or metabolic stability. In contrast, the impact of N-terminal acetylation for the majority of the proteome, and its combinatorial contributions to phenotypes, are unknown. Here, by studying the yeast prion [PSI(+)], an amyloid of the Sup35 protein, we show that loss of N-terminal acetylation promotes general protein misfolding, a redeployment of chaperones to these substrates, and a corresponding stress response. These proteostasis changes, combined with the decreased stability of unacetylated Sup35 amyloid, reduce the size of prion aggregates and reverse their phenotypic consequences. Thus, loss of N-terminal acetylation, and its previously unanticipated role in protein biogenesis, globally resculpts the proteome to create a unique phenotype.
- Klaips, C. L., Hochstrasser, M. L., Langlois, C. R., & Serio, T. R. (2014). Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing. eLife, 3.More infoThe proteostasis network has evolved to support protein folding under normal conditions and to expand this capacity in response to proteotoxic stresses. Nevertheless, many pathogenic states are associated with protein misfolding, revealing in vivo limitations on quality control mechanisms. One contributor to these limitations is the physical characteristics of misfolded proteins, as exemplified by amyloids, which are largely resistant to clearance. However, other limitations imposed by the cellular environment are poorly understood. To identify cell-based restrictions on proteostasis capacity, we determined the mechanism by which thermal stress cures the [PSI(+)]/Sup35 prion. Remarkably, Sup35 amyloid is disassembled at elevated temperatures by the molecular chaperone Hsp104. This process requires Hsp104 engagement with heat-induced non-prion aggregates in late cell-cycle stage cells, which promotes its asymmetric retention and thereby effective activity. Thus, cell division imposes a potent limitation on proteostasis capacity that can be bypassed by the spatial engagement of a quality control factor.
- Pezza, J. A., Villali, J., Sindi, S. S., & Serio, T. R. (2014). Amyloid-associated activity contributes to the severity and toxicity of a prion phenotype. Nature communications, 5, 4384.More infoThe self-assembly of alternative conformations of normal proteins into amyloid aggregates has been implicated in both the acquisition of new functions and in the appearance and progression of disease. However, while these amyloidogenic pathways are linked to the emergence of new phenotypes, numerous studies have uncoupled the accumulation of aggregates from their biological consequences, revealing currently underappreciated complexity in the determination of these traits. Here, to explore the molecular basis of protein-only phenotypes, we focused on the Saccharomyces cerevisiae Sup35/[PSI(+)] prion, which confers a translation termination defect and expression level-dependent toxicity in its amyloid form. Our studies reveal that aggregated Sup35 retains its normal function as a translation release factor. However, fluctuations in the composition and size of these complexes specifically alter the level of this aggregate-associated activity and thereby the severity and toxicity of the amyloid state. Thus, amyloid heterogeneity is a crucial contributor to protein-only phenotypes.
- DiSalvo, S., & Serio, T. R. (2011). Insights into prion biology: Integrating a protein misfolding pathway with its cellular environment. Prion, 5(2), 76-83.More infoPMID: 21654204;PMCID: PMC3166505;Abstract: Protein misfolding and assembly into ordered, self-templating aggregates (amyloid) has emerged as a novel mechanism for regulating protein function. For a subclass of amyloidogenic proteins known as prions, this process induces transmissible changes in normal cellular physiology, ranging from neurodegenerative disease in animals and humans to new traits in fungi. The severity and stability of these altered phenotypic states can be attenuated by the conformation or amino-acid sequence of the prion, but in most of these cases, the protein retains the ability to form amyloid in vitro. Thus, our ability to link amyloid formation in vitro with its biological consequences in vivo remains a challenge. In two recent studies, we have begun to address this disconnect by assessing the effects of the cellular environment on traits associated with the misfolding of the yeast prion Sup35. Remarkably, the effects of quality control pathways and of limitations on protein transfer in vivo amplify the effects of even slight differences in the efficiency of Sup35 misfolding, leading to dramatic changes in the associated phenotype. Together, our studies suggest that the interplay between protein misfolding pathways and their cellular context is a crucial contributor to prion biology.
- Disalvo, S., Derdowski, A., Pezza, J. A., & Serio, T. R. (2011). Dominant prion mutants induce curing through pathways that promote chaperone-mediated disaggregation. Nature Structural and Molecular Biology, 18(4), 486-493.More infoPMID: 21423195;PMCID: PMC3082495;Abstract: Protein misfolding underlies many neurodegenerative diseases, including the transmissible spongiform encephalopathies (prion diseases). Although cells typically recognize and process misfolded proteins, prion proteins evade protective measures by forming stable, self-replicating aggregates. However, coexpression of dominant-negative prion mutants can overcome aggregate accumulation and disease progression through currently unknown pathways. Here we determine the mechanisms by which two mutants of the Saccharomyces cerevisiae Sup35 protein cure the [PSI+] prion. We show that both mutants incorporate into wild-type aggregates and alter their physical properties in different ways, diminishing either their assembly rate or their thermodynamic stability. Whereas wild-type aggregates are recalcitrant to cellular intervention, mixed aggregates are disassembled by the molecular chaperone Hsp104. Thus, rather than simply blocking misfolding, dominant-negative prion mutants target multiple events in aggregate biogenesis to enhance their susceptibility to endogenous quality-control pathways. © 2011 Nature America, Inc. All rights reserved.
- Tuite, M. F., & Serio, T. R. (2011). Conformational conversion and prion disease: Authors' reply. Nature Reviews Molecular Cell Biology, 12(4), 273-.
- Derdowski, A., Sindi, S. S., Klaips, C. L., DiSalvo, S., & Serio, T. R. (2010). A size threshold limits prion transmission and establishes phenotypic diversity. Science, 330(6004), 680-683.More infoPMID: 21030659;PMCID: PMC3003433;Abstract: According to the prion hypothesis, atypical phenotypes arise when a prion protein adopts an alternative conformation and persist when that form assembles into self-replicating aggregates. Amyloid formation in vitro provides a model for this protein-misfolding pathway, but the mechanism by which this process interacts with the cellular environment to produce transmissible phenotypes is poorly understood. Using the yeast prion Sup35/[PSI+], we found that protein conformation determined the size distribution of aggregates through its interactions with a molecular chaperone. Shifts in this range created variations in aggregate abundance among cells because of a size threshold for transmission, and this heterogeneity, along with aggregate growth and fragmentation, induced age-dependent fluctuations in phenotype. Thus, prion conformations may specify phenotypes as population averages in a dynamic system.
- Tuite, M. F., & Serio, T. R. (2010). The prion hypothesis: From biological anomaly to basic regulatory mechanism. Nature Reviews Molecular Cell Biology, 11(12), 823-833.More infoPMID: 21081963;PMCID: PMC3003427;Abstract: Prions are unusual proteinaceous infectious agents that are typically associated with a class of fatal degenerative diseases of the mammalian brain. However, the discovery of fungal prions, which are not associated with disease, suggests that we must now consider the effect of these factors on basic cellular physiology in a different light. Fungal prions are epigenetic determinants that can alter a range of cellular processes, including metabolism and gene expression pathways, and these changes can lead to a range of prion-associated phenotypes. The mechanistic similarities between prion propagation in mammals and fungi suggest that prions are not a biological anomaly but instead could be a newly appreciated and perhaps ubiquitous regulatory mechanism. © 2010 Macmillan Publishers Limited. All rights reserved.
- Pezza, J. A., Langseth, S. X., Yamamoto, R. R., Doris, S. M., Ulin, S. P., Salomon, A. R., & Serio, T. R. (2009). The NatA acetyltransferase couples sup35 prion complexes to the [PSI +] Phenotype. Molecular Biology of the Cell, 20(3), 1068-1080.More infoPMID: 19073888;PMCID: PMC2633373;Abstract: Protein-only (prion) epigenetic elements confer unique phenotypes by adopting alternate conformations that specify new traits. Given the conformational flexibility of prion proteins, protein-only inheritance requires efficient self-replication of the underlying conformation. To explore the cellular regulation of conformational self-replication and its phenotypic effects, we analyzed genetic interactions between [PSI +], a prion form of the S. cerevisiae Sup35 protein (Sup35 PSI+), and the three N a-acetyltransferases, NatA, NatB, and NatC, which collectively modify ∼50% of yeast proteins. Although prion propagation proceeds normally in the absence of NatB or NatC, the [PSI +] phenotype is reversed in strains lacking NatA. Despite this change in phenotype, [PSI +] NatA mutants continue to propagate heritable Sup35 [PSI+]. This uncoupling of protein state and phenotype does not arise through a decrease in the number or activity of prion templates (propagons) or through an increase in soluble Sup35. Rather, NatA null strains are specifically impaired in establishing the translation termination defect that normally accompanies Sup35 incorporation into prion complexes. The NatA effect cannot be explained by the modification of known components of the [PSI +] prion cycle including Sup35; thus, novel acetylated cellular factors must act to establish and maintain the tight link between Sup35 [PSI+] complexes and their phenotypic effects. © 2009 by The American Society for Cell Biology.
- Sindi, S. S., & Serio, T. R. (2009). Prion dynamics and the quest for the genetic determinant in protein-only inheritance. Current Opinion in Microbiology, 12(6), 623-630.More infoPMID: 19864176;PMCID: PMC2846611;Abstract: According to the prion hypothesis, proteins may act in atypical roles as genetic elements of infectivity and inheritance by undergoing self-replicating changes in physical state. While the preponderance of evidence strongly supports this concept particularly in fungi, the detailed mechanisms by which distinct protein forms specify unique phenotypes are emerging concepts. A particularly active area of investigation is the molecular nature of the heritable species, which has been probed through genetic, biochemical, and cell biological experimentation as well as by mathematical modeling. Here, we suggest that these studies are converging to implicate small aggregates composed of prion-state conformers as the transmissible genetic determinants of protein-based phenotypes. © 2009 Elsevier Ltd. All rights reserved.
- Pezza, J. A., & Serio, T. R. (2007). Prion propagation: the role of protein dynamics.. Prion, 1(1), 36-43.More infoPMID: 19164914;PMCID: PMC2633706;Abstract: The transfer of phenotypes from one individual to another is a fundamental aspect of biology. In addition to traditional nucleic acid-based genetic determinants, unique proteins known as prions can also act as elements of inheritance, infectivity, and disease. Nucleic acids and proteins encode genetic information in distinct ways, either in the sequence of bases in DNA or RNA or in the three dimensional structure of the polypeptide chain. Given these differences in the nature of the genetic repository, the mechanisms underlying the transmission of nucleic acid-based and protein-based phenotypes are necessarily distinct. While the appearance, persistence and transfer of nucleic acid determinants require the synthesis of new polymers, recent studies indicate that prions are propagated through dynamic transitions in the structure of existing protein.
- Satpute-Krishnan, P., Langseth, S. X., & Serio, T. R. (2007). Hsp104-dependent remodeling of prion complexes mediates protein-only inheritance. PLoS biology, 5(2), e24.More infoInheritance of phenotypic traits depends on two key events: replication of the determinant of that trait and partitioning of these copies between mother and daughter cells. Although these processes are well understood for nucleic acid-based genes, the mechanisms by which protein-only or prion-based genetic elements direct phenotypic inheritance are poorly understood. Here, we report a process crucial for inheritance of the Saccharomyces cerevisiae prion [PSI(+)], a self-replicating conformer of the Sup35 protein. By tightly controlling expression of a Sup35-GFP fusion, we directly observe remodeling of existing Sup35([PSI+]) complexes in vivo. This dynamic change in Sup35([PSI+]) is lost when the molecular chaperone Hsp104, a factor essential for propagation of all yeast prions, is functionally impaired. The loss of Sup35([PSI+]) remodeling by Hsp104 decreases the mobility of these complexes in the cytosol, creates a segregation bias that limits their transmission to daughter cells, and consequently diminishes the efficiency of conversion of newly made Sup35 to the prion form. Our observations resolve several seemingly conflicting reports on the mechanism of Hsp104 action and point to a single Hsp104-dependent event in prion propagation.
- Satpute-Krishnan, P., & Serio, T. R. (2005). Prion protein remodelling confers an immediate phenotypic switch. Nature, 437(7056), 262-265.More infoPMID: 16148935;Abstract: In a variety of systems, proteins have been linked to processes historically limited to nucleic acids, such as infectivity and inheritance. These atypical proteins, termed prions, lack sequence homology but are collectively defined by their capacity to adopt multiple physical and therefore functional states in vivo. Newly synthesized prion protein generally adopts the form already present in the cell, and this in vivo folding bias directs the near faithful transmission of the corresponding phenotypic state. Switches between the prion and non-prion phenotypes can occur in vivo; however, the fate of existing protein during these transitions and its effects on the emergence of new traits remain major unanswered questions. Here, we determine the changes in protein-state that induce phenotypic switching for the yeast prion Sup35/[PSI+]. We show that the prion form does not need to be specified by an alternate misfolding pathway initiated during Sup35 synthesis but instead can be accessed by mature protein. This remodelling of protein from one stable form to another is accompanied by the loss of Sup35 activity, evoking a rapid change in cellular phenotype within a single cell cycle. © 2005 Nature Publishing Group.
- Serio, T. R., & Lindquist, S. L. (2001). The yeast prion [PSI+]: molecular insights and functional consequences. Advances in protein chemistry, 59, 391-412.
- Serio, T. R., & Lindquist, S. L. (2001). [PSI+], SUP35, and chaperones. Advances in protein chemistry, 57, 335-66.More infoBiochemical characterization of the yeast prions has revealed many similarities with the mammalian amyloidogenic proteins. The ease of generating in vivo mutations in yeast and the developing in vitro models for [PSI+] and [URE3] circumvent many of the difficulties of studying the proteins linked to the mammalian amyloidoses. Future work especially aimed at understanding the molecular role of chaperone proteins in regulating conversion as well as the early steps in de novo formation of the prion state in yeast will likely provide invaluable lessons that may be more broadly applicable to related processes in higher eukaryotes. It is important to remember, however, that there are clear distinctions between disease states associated with amyloidogenesis and the epigenetic modulation of protein function by self-perpetuating conformational conversions. Amyloid formation is detrimental to mammals and is likely selected against, providing a possible explanation for the late onset of these disorders (Lansbury, 1999). In contrast, the known yeast prions are compatible with normal growth and, if beneficial to the organism, may be subject to evolutionary pressures that ultimately maximize transmission. In the prion proteins examined to date, distinct domains are responsible for normal function and for the conformational switches producing a prion conversion of that function. Recent work has demonstrated that the prion domains are both modular and transferable to other proteins on which they can confer a heritable epigenetic alteration of function (Edskes et al., 1999; Li and Lindquist, 2000; Patino et al., 1996; Santoso et al., 2000; Sondheimer and Lindquist, 2000). That is, prion domains need not coevolve with particular functional domains but might be moved from one protein to another during evolution. Such processes may be widely used in biology. Mechanistic studies of [PSI+] and [URE3] replication are sure to lay a foundation of knowledge for understanding a host of nonconventional genetic elements that currently remain elusive.
- Serio, T. R., Cashikar, A. G., Kowal, A. S., Sawicki, G. J., & Lindquist, S. L. (2001). Self-perpetuating changes in Sup35 protein conformation as a mechanism of heredity in yeast. Biochemical Society symposium, 35-43.More infoRecently, a novel mode of inheritance has been described in the yeast Saccharomyces cerevisiae. The mechanism is based on the prion hypothesis, which posits that self-perpetuating changes in the conformation of single protein, PrP, underlie the severe neurodegeneration associated with the transmissible spongiform enchephalopathies in mammals. In yeast, two prions, [URE3] and [PSI+], have been identified, but these factors confer unique phenotypes rather than disease to the organism. In each case, the prion-associated phenotype has been linked to alternative conformations of the Ure2 and Sup35 proteins. Remarkably, Ure2 and Sup35 proteins existing in the alternative conformations have the unique capacity to transmit this physical state to the newly synthesized protein in vivo. Thus, a mechanism exists to ensure replication of the conformational information that underlies protein-only inheritance. We have characterized the mechanism by which Sup35 conformational information is replicated in vitro. The assembly of amyloid fibres by a region of Sup35 encompassing the N-terminal 254 amino acids faithfully recapitulates the in vivo propagation of [PSI+]. Mutations that alter [PSI+] inheritance in vivo change the kinetics of amyloid assembly in vitro in a complementary fashion, and lysates from [PSI+] cells, but not [psi-] cells, accelerate assembly in vitro. Using this system we propose a mechanism by which the alternative conformation of Sup35 is adopted by an unstructured oilgomeric intermediate at the time of assembly.
- Serio, T. R., & Lindquist, S. L. (2000). Protein-only inheritance in yeast: Something to get [PSI+]-ched about. Trends in Cell Biology, 10(3), 98-105.More infoPMID: 10675903;Abstract: Recent work suggests that two unrelated phenotypes, [PSI+] and [URE3], in the yeast Saccharomyces cerevisiae are transmitted by non-covalent changes in the physical states of their protein determinants, Sup35p and Ure2p, rather than by changes in the genes that encode these proteins. The mechanism by which alternative protein states are self-propagating is the key to understanding how proteins function as elements of epigenetic inheritance. Here, we focus on recent molecular-genetic analysis of the inheritance of the [PSI+] factor of S. cerevisiae. Insights into this process might be extendable to a group of mammalian diseases (the amyloidoses), which are also believed to be a manifestation of self-perpetuating changes in protein conformation.
- Serio, T. R., Cashikar, A. G., Kowal, A. S., Sawicki, G. J., Moslehi, J. J., Serpell, L., Arnsdorf, M. F., & Lindquist, S. L. (2000). Nucleated conformational conversion and the replication of conformational information by a prion determinant. Science (New York, N.Y.), 289(5483), 1317-21.More infoPrion proteins can serve as genetic elements by adopting distinct physical and functional states that are self-perpetuating and heritable. The critical region of one prion protein, Sup35, is initially unstructured in solution and then forms self-seeded amyloid fibers. We examined in vitro the mechanism by which this state is attained and replicated. Structurally fluid oligomeric complexes appear to be crucial intermediates in de novo amyloid nucleus formation. Rapid assembly ensues when these complexes conformationally convert upon association with nuclei. This model for replicating protein-based genetic information, nucleated conformational conversion, may be applicable to other protein assembly processes.
- Serio, T. R., & Lindquist, S. L. (1999). [PSI+]: an epigenetic modulator of translation termination efficiency. Annual review of cell and developmental biology, 15, 661-703.More infoThe [PSI+] factor of the yeast Saccharomyces cerevisiae is an epigenetic regulator of translation termination. More than three decades ago, genetic analysis of the transmission of [PSI+] revealed a complex and often contradictory series of observations. However, many of these discrepancies may now be reconciled by a revolutionary hypothesis: protein conformation-based inheritance (the prion hypothesis). This model predicts that a single protein can stably exist in at least two distinct physical states, each associated with a different phenotype. Propagation of one of these traits is achieved by a self-perpetuating change in the protein from one form to the other. Mounting genetic and biochemical evidence suggests that the determinant of [PSI+] is the nuclear encoded Sup35p, a component of the translation termination complex. Here we review the series of experiments supporting the yeast prion hypothesis and provide another look at the 30 years of work preceding this theory in light of our current state of knowledge.
- Serio, T. R., Cashikar, A. G., Moslehi, J. J., Kowal, A. S., & Lindquist, S. L. (1999). Yeast prion [psi +] and its determinant, Sup35p. Methods in enzymology, 309, 649-73.
- Lindquist, S., DebBurman, S. K., Glover, J. R., Kowal, A. S., Liu, J. J., Schirmer, E. C., & Serio, T. R. (1998). Amyloid fibres of Sup35 support a prion-like mechanism of inheritance in yeast. Biochemical Society transactions, 26(3), 486-90.
- Serio, T. R., Cahill, N., Prout, M. E., & Miller, G. (1998). A functionally distinct TATA box required for late progression through the Epstein-Barr virus life cycle. Journal of virology, 72(10), 8338-43.More infoDuring EBV infection, lytic DNA replication activates late gene expression in trans via an uncharacterized pathway. In this study, we mapped the target of this regulatory cascade to a variant TATA box (TATTAAA) and the 3' flanking region within the core promoter of the BcLF1 gene. The inherent late activity of this core promoter is, surprisingly, disrupted by a heterologous enhancer, suggesting that late gene expression is regulated through core promoter sequences located in a transcriptionally inert environment.
- Serio, T. R., Kolman, J. L., & Miller, G. (1997). Late gene expression from the Epstein-Barr virus BclF1 and BFRF3 promoters does not require DNA replication in cis. Journal of Virology, 71(11), 8726-8734.More infoPMID: 9343231;PMCID: PMC192337;Abstract: Late gene expression follows and is dependent upon lyric replication of the vital genome. Although experimental evidence is lacking, lytic viral DNA replication is believed to remove modifications or binding factors from the genome which serve to repress late gene expression during latency or the early lytic cycle. We have developed a reporter assay to begin characterizing the mechanisms that regulate late gene expression in Epstein-Barr virus (EBV). In this model system, the activities of late promoter-reporter fusions are measured following transient transfection into tissue culture cells expressing EBV during different stages of the lytic cycle. This system faithfully recapitulates late expression patterns from the endogenous virus, implicating specific cis-active sequences in the control of late gene expression. In addition, these promoters respond only indirectly to the viral immediate-early transactivator, ZEBRA. This indirect response is mediated by other viral or virally induced activities downstream of ZEBRA in the lyric cascade. In this system, late gene expression is sensitive to inhibitors of the viral DNA polymerase such as phosphonoacetic acid, although the reporters lack a eukaryotic origin of replication and are not replicated under the assay conditions. Thus, replication of the transcriptional template is not a prerequisite for expression with late kinetics, a finding inconsistent with the current models which posit a cis-active relationship between lytic EBV DNA replication and late gene expression. Rather, analysis of this system has revealed a trans relationship between late gene expression and viral DNA replication and highlights the indirect and complex link between these two events.
- Serio, T. R., Angelont, A., Kolman, J. L., Gradoville, L., Sun, R., Katz, D. A., Grunsven, W. V., Middeldorp, J., & Miller, G. (1996). Two 21-kilodalton components of the Epstein-Barr virus capsid antigen complex and their relationship to ZEBRA-associated protein p21 (ZAP21). Journal of Virology, 70(11), 8047-8054.More infoPMID: 8892929;PMCID: PMC190878;Abstract: The viral capsid antigen complex of Epstein-Barr virus (EBV), an important serodiagnostic marker of infection with the virus, consists of at least four components, with molecular masses of 150, 110, 411, and 21 kDa. Here we show that the 21-kDa component of the viral capsid antigen consists of products of two EBV genes, BFRF3 and BLRF2. Both products were expressed from late transcripts, were recognized by human antisera, and were present in virions. The BFRF3 product, but not that of BLRF2, fulfilled the definition of ZEBRA-associated protein p21 (ZAP21). In cells in which EBV was lytically replicating, BFRF3 protein was coimmunoprecipitated together with ZEBRA by a rabbit antiserum directed against amino acids 197 to 245 of BZLF1. In EBV- negative cells cotransfected with BZLF1 and BFRF3 expression vectors, BFRF3 was also coimmunoprecipitated with this antiserum. Although this antiserum could not detect BFRF3 on an immunoblot, it was able to immunoprecipitate BFRF3 in the absence of ZEBRA expression. The rabbit antiserum to amino acids 197 to 245 of BZLF1 was found to detect the same epitope at the carboxy end of BFRF3 as was recognized by rabbit antiserum to BFRF3 itself. Thus, coimmunoprecipitation of BFRF3 p21 with ZEBRA appeared to be due to cross- reactivity of the immunoprecipitating antiserum rather than to direct association of ZEBRA and BFRF3 p21.
- Serio, T. R. (2017, Jan). Prion Biology: At the Interface Between Prion Misfolding and Its Cellular Environment. research seminar. Amherst, MA: UMass-Amherst.
- Serio, T. R. (2016, Dec). Prion Biology: At the Interface of Protein Misfolding and Its Cellular Environment. ASCB Annual Meeting. San Francisco, CA: ASCB.
- Serio, T. R. (2016, July). Prion Biology: At the Intersection of Protein Misfolding and Cellular Proteostasis. Protein Society Annual Meeting. Baltimore, MD: Protein Society.
- Serio, T. R. (2016, May). How Do Proteins Act As Genetic Elements. Math-Bio Workshop. Merced, CA: UC-Merced.
- Serio, T. R. (2015, April). Prion Biology: Understanding the Intersection of Protein Misfolding with Its Cellular Enviroment. Seminar. Richmond, VA: Virgina Commonwealth University.
- Serio, T. R. (2015, June). Prion Initiation: A Multistep, Chaperone-Regulated Pathway In Vivo. Molecular Mechanisms and Physiological Consequences of Protein Aggregation. West Palm Beach, FL: FASEB SRC.
- Serio, T. R. (2015, May). Prion Initiation: A Multistep, Chaperone-Regulated Pathway In Vivo. Prion 2015. Fort Collins, CO.
- Serio, T. R. (2014, March). Prion Biology: Understanding the Intersection of Protein Misfolding with Its Cellular Enviroment. SeminarIndiana University - Purdue University, Department of Biology.
- Serio, T. R. (2014, May). Prion Initiation: A Multistep, Chaperone-Regulated Pathway In Vivo. Molecular Chaperones and Stress Responses. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory.
- Serio, T. R. (2013, April). Amyloid Dynamics in vivo and the Generation of Novel Protein-Based Phenotypes. Conferences Jacques Monod: Protein misfolding and aggregation in ageing and disease. Brest, France: CNRS.
- Serio, T. R. (2013, December). The interplay among general protein misfolding, the cellular stress response, and cell division regulates prion propagation. Amercan Society for Cell Biology. New Orleans, LA: ASCB.
- Serio, T. R. (2013, February). Insights into Prion Biology: Protein Misfolding in Its Cellular Environment. Seminar. Easton, PA: Lafayette College.
- Serio, T. R. (2012, April). Insights into Prion Biology: Protein Misfolding in Its Cellular Environment. American Society for Biochemistry and Molecular Biology. San Diego, CA: ASBMB.
- Serio, T. R. (2012, March). Insights into Prion Biology: Protein Misfolding in Its Cellular Environment. Seminar. Providence, RI: Rhode Island College.