Honors and Awards 1125

The 2008 Society of America Medal

Susan Lindquist

Susan Lindquist

HE 2008 recipient of of and transcriptional mechanisms, making it the stron- T America Medal is Susan Lindquist. Lindquist has gest most global change in eukaryotic gene expression completely transformed our understanding of the role known (McKenzie et al. 1975; McKenzie and Meselson of folding in biological systems. Her work has 1977; Lindquist 1980, 1981). She also discovered that employed, and to great effect, a zoo of powerful genetic eukaryotic cells have the unexpected capacity to discri- systems, including , fruit flies, Arabidopsis, and minate between coexisting mRNAs and independently mice. She is also a fearless biochemist, employing state regulate their translation. During heat shock they of the art technologies and inventing new ones. Again translate heat-shock mRNAs with high efficiency and and again, she has shown the power of to block normal mRNAs from translation, yet hold them expand and explicate fundamental insights gained from ready for reactivation after heat shock (McKenzie et al. genetic analysis and the power of genetics to disentangle 1975; Lindquist 1980, 1981; DiDomenico et al. 1982). intractable problems in biochemistry. Her work has In a seminal series of experiments Lindquist contin- provided paradigm-shifting insights into the most basic ued to exploit the heat-shock response to establish how aspects of cell biology, genetics, and evolution. intricate and highly orchestrated the regulation of eu- karyotic gene expression can be. Her work revealed regulation operating at the level of RNA splicing (Yost HEAT-SHOCK RESPONSE, HEAT-SHOCK , and Lindquist 1986, 1988, 1991), selective RNA and AND STRESS TOLERANCE protein transport in and out of the nucleus (Velazquez Lindquist’s work began with studies of the heat-shock et al. 1980; Wang and Lindquist 1998), selective RNA response when she was a graduate student at Harvard in degradation (Petersen and Lindquist 1988, 1989), ’s lab. (At that time she published and selective deadenylation (Dellavalle et al. 1994). under the name Susan McKenzie.) As a second-year Her group also established that it is the heat-shock student, she was casting about for a new project when proteins themselves that turn these mechanisms off, at she bumped into a new assistant professor in the hallway every level (Yost and Lindquist 1986, 1991; Dellavalle of the biology labs. Sally Elgin told her of some exciting et al. 1994; Vogel et al. 1995). As it became clear that new work by Tissiers and Mitchell: that proteins were heat-shock proteins help to prevent and repair the made in response to heat shock in the salivary glands of damage caused by stress (a story to which Lindquist fruit flies. Lindquist decided to see if tissue culture cells also made important contributions), the extremely had the same response, which would make it tractable to elegant logic of the regulatory circuitry was revealed: as molecular analysis and provide a powerful wedge to ex- heat-shock proteins (Hsps) restore normal protein ho- plore the then murky waters of eukaryotic gene regula- meostasis they reset the damaged regulatory systems tion (McKenzie et al. 1975; McKenzie and Meselson that prevent the transcription, translation, splicing, 1977). She discovered that these cells did have the degradation, and deadenylation of normal mRNAs. By response and that it was governed by both translational restoring regulatory systems to their normal state, Hsps 1126 Honors and Awards remove their own advantage, turning off the response. lished that it was an inherent property of Sup35 itself. Due in large measure to her work (complimented by Remarkably, once a small fraction switches, it rapidly the seminal work of Spradling, Pelham, Lis, and Wu on templates the conversion of other proteins to the same transcription), the heat-shock response provides per- state. Prion1 cell lysates can template this conversion, haps the most beautiful and complete example of but not lysates. This work established the funda- eukaryotic gene regulation documented. mental biochemical mechanism for protein-based in- Turning her attention to the function of the induced heritance (Glover et al. 1997; Serio et al. 2000). More proteins, in collaboration with Didier Picard in Keith recently, Lindquist has provided stunning insight into Yamamoto’s group, Lindquist established that is the previously mysterious complexities of prion strains required for the maturation of steroid hormone recep- (Krishnan and Lindquist 2005; Mukhopadhyay et al. tors and oncogenic tyrosine kinases (Picard et al. 1990; 2007; Tessier and Lindquist 2007). Xu and Lindquist 1993; Xu et al. 1999). Since Hsp90 is Sup35 is an essential translation termination factor. complexed with the inactive forms of these proteins, Its prion domain has conserved the ability to switch into previous assumptions had been that Hsp90 acted to an inactive prion state for 800 million years of evolution. repress their function. This paradigm shift, established Lindquist argues that this switch is not just a disease of through genetic analysis, was complemented by con- yeast, but serves as a completely novel mechanism for temporaneous work on the biochemistry of the protein creating phenotypic diversity. When cells switch to the by Pratt and Toft and has held true for countless other prion state the loss of termination activity leads to the metastable proteins that regulate key processes in growth, read-through of stop codons, creating a host of new differentiation, development, and cancer. , many of which are advantageous. By re- Next, Lindquist’s group discovered the tolerance fac- vealing previously hidden genetic variation on a global, tor that defends cells against extreme stresses. A single genomewide scale the prion allows survival in fluctuat- protein, Hsp104, increases survival up to 10,000-fold ing environments and can thereby provide a route to the (Sanchez and Lindquist 1990; Sanchez et al. 1992). rapid evolution of complex traits (True and Lindquist Using genetics and biochemistry to decipher its mech- 2000; True et al. 2004). anism, her group turned another long-held assumption Collaborating with the laboratory of , on its head. Proteins that are denatured and even mas- Lindquist was also instrumental in establishing that sively aggregated do not need to be degraded after another prion might serve a beneficial purpose (Si et al. stress: using the energy of ATP, and with the aid of two 2003). CPEB, which plays a key role in the maintenance chaperones, Hsp70 and hsp40, Hsp104 restores these of synapses in metazoan brains, has a prion-like ability to proteins to function (Parsell et al. 1994; Glover and sustain itself in an altered self-perpetuating conforma- Lindquist 1998). tion much like the yeast prion. Since the prion is the active form of the protein, their results suggest that this self-sustaining conformation constitutes a ‘‘molecular memory’’ for maintaining synapses. This paradigm- AND INHERITANCE shifting work has greatly expanded our view of the In 1994 Reed Wickner made the remarkable sugges- importance of self-sustaining changes in protein con- tion that a mysterious, cytoplasmically inherited factor formation in biological systems. known as ½PSI1 might be based upon some sort of self-perpetuating protein state and named it a prion. In collaborationwithChernoffandLeibman,Lindquistestab- HSP90 AND EVOLUTION lished that Hsp104 regulates the propagation of ½PSI1. Having found that Hsp104 is a protein-remodeling fac- Hsp90’s role in the maturation of steroid receptors tor, this provided a strong genetic argument in support of and oncogenic tryosine kinases (discovered by Lind- inheritance based on protein conformation (Chernoff quist’s group in collaboration with Yamamoto’s, see et al. 1995). above) has now been confirmed for a wide variety of Lindquist’s group went on to provide much of the key metastable signal transducers. This places the protein in genetic, cell biological, and biochemical evidence that a unique position to couple environmental contingency established that proteins can serve as elements of ge- with evolutionary change. In the mid-1990s, Lindquist’s netic inheritance. They showed that the protein Sup35 lab made the stunning discovery that Hsp90 buffers vast transitions from a soluble to an aggregated state in form- amounts of naturally occurring genetic variation in fruit ing the prion and that this state is self propagating by the flies (Rutherford and Lindquist 1998). By robustly transmission of protein aggregates from mother cells to maintaining diverse signaling pathways Hsp90 allows a their daughters (Patino et al. 1996). multitude of to accumulate in a silent state. Next, they determined the nature of the conforma- When the organism experiences protein homeostatic tional switch—from a natively disordered state to an stress (e.g., growth at high temperature), the variants are amyloid filament—and, using purified protein, estab- exposed, creating new traits. The variation can then be Honors and Awards 1127 enriched by selective breeding and the phenotypes lytic pathways. Lindquist’s group recently found that retained, even when the environment has returned to these same mechanisms are subverted by cancer cells to normal. Recently Lindquist’s lab extended this work promote their survival in the face of the multifarious to Arabidopsis, demonstrating that Hsp90’s capacity to stresses of deranged signaling, genetic mutations, an- buffer and release genetic variation is conserved across oxia, nutrient deprivation, and the stress of new envi- enormous evolutionary distances (Queitsch et al. 2002, ronments. Working with mice and with human cancer 2008; Sangster et al. 2008a,b). cells driven by diverse oncogenic lesions, their work The Lindquist lab’s studies of Hsp90 provided the provides fundamental new insight on the ‘‘nononco- first molecular foundation for the decades-old theory of gene’’ addiction of cancer cells. It also suggests that HSF canalization: that development can be made insensitive may be a powerful therapeutic target, aimed at the uni- to genetic variation. In one fell swoop, it also explained que biology of cancer cells rather than at any particular how that variation could be exposed by environmental oncogenic lesion (Dai et al. 2007). stress (which overwhelms protein homeostasis). The mechanism can produce an extraordinary variety of GENETIC TRICKS TO REMODEL traits, reveals variation on a global genomewide scale, and allows that variation to work in a combinatorial Lindquist’s laboratory has also had an important fashion. This stunning new concept can also be applied impact on biological research in devising several power- to other biological problems, such as the evolution of ful new technologies. From the standpoint of genetics, tumors within a host (Rutherford and Lindquist one of the most important has been the development of 1998; Queitsch et al. 2002; Sangster et al. 2004). heterologous, site-specific recombinases to precisely Lindquist pointed the way to that extension herself, remodel genomes in living organisms. Kent Golic, a when she reported that the mutations that activate an postdoc in the Lindquist laboratory, imported a yeast oncogenic protein also makes it more dependent upon site-specific DNA recombinase, FLP, into flies and Hsp90 for folding (Xu and Lindquist 1993; Xu et al. embedded genes containing FLP target sites in the fly 1999). , providing the first mechanism for precisely popping genes in and out of the genome in a higher organism. The method also provided a mechanism for AND HUMAN DISEASE inducing sister chromatid and homologous chromo- Susan Lindquist has also provided new insights on the some exchange at specific sites to generate an allelic multifaceted roles that protein homeostasis plays in series of insertions (Golic and Lindquist 1989; Welte human diseases. et al. 1993; Golic et al. 1997). This work transformed the Reasoning that many neurodegenerative diseases are practice of Drosophila genetics and has been used by due to problems in protein folding and trafficking, and countless labs to develop new methods for screening moreover that these problems and the mechanisms for and for cell fate and lineage analysis. It also strongly coping with them are universal, Lindquist’s group is influenced the development of site-specific recombina- employing yeast cells as ‘‘living test tubes’’ to study the tion systems in other organisms, such as the Cre/Lox cellular basis of complex diseases, such as Huntington’s system in mice. chorea (huntingtin) and Parkinson’s disease (a- In reviewing Susan Lindquist’s numerous scientific synuclein) (Krobitsch and Lindquist 2000; Outeiro contributions, one is overwhelmed by the breadth, and Lindquist 2003). They have used these cells to diversity, and endless creativity of this scientist. Her discover several unexpected properties of the impli- research group opened up the molecular analysis of the cated proteins. Importantly, although these diseases are heat-shock response, provided definitive evidence that characterized by protein aggregation, the factors that heat-shock proteins are key to tolerance to stress, govern their toxicity show virtually no overlap. Remark- established a new model for the general mechanism of ably, many of the factors discovered in yeast have now amyloid formation, provided evidence for mechanisms been validated in neurons. They have also discovered by which complex traits could evolve rapidly, created potential new therapeutic strategies that are currently model systems for studying deadly neurodegenerative being tested (Cashikar et al. 2005; Cooper et al. 2006; diseases in yeast, and provided the first plausible Duennwald et al. 2006a,b). molecular explanation for self-perpetuating protein Once again demonstrating her potential to blaze new conformational changes that might also be responsible trails, Lindquist’s group has recently revealed another for prion diseases in man. Lindquist is not limited to pivotal role that protein homeostasis plays in balancing being an exceptional, groundbreaking scientist. In health and disease. HSF, the main regulator of the heat- addition to her spectacular research, she has demon- shock response, controls a host of survival mechanisms, strated a deep commitment to young scientists’ careers including protein homeostasis, maintenance of signal- and to advancing women in science by serving both as a ing pathways, prevention of apoptosis, responses to role model and an advocate, speaking frequently on this growth factors, and flux through respiratory and glyco- topic. For all these reasons the Genetics Society is 1128 Honors and Awards honored to salute Susan Lindquist for her impact on her Patino, M. M., J.-J. Liu,J.R.Glover and S. Lindquist, field and our profession. 1996 Support for the prion hypothesis for inheritance of a phe- notypic trait in yeast. Science 273: 622–626. Petersen, R., and S. Lindquist, 1989 Regulation of HSP70 synthe- sis by messenger RNA degradation. Cell Regul. 1: 135–149. LITERATURE CITED Petersen, R. B., and S. Lindquist, 1988 The Drosophila hsp70 mes- ashikar uennwald indquist sage is rapidly degraded at normal temperatures and stabilized by C , A. G., M. D and S. L. L , 2005 A chap- heat shock. Gene 72: 161–168. erone pathway in protein disaggregation: Hsp26 alters the nature Picard, D., B. Khursheed,M.J.Garabadian,M.G.Fortin,S.Lind- of protein aggregates to facilitate reactivation by hsp104. J. Biol. quist et al., 1990 Reduced levels of hsp90 compromise receptor Chem. 280: 23869–23875. action in vivo. Nature 348: 166–168. Chernoff, Y. O., S. L. Lindquist, B.-I. Ono,S.G.Inge-Vechtomov ueitsch angster indquist iebman Q , C., T. A. S and S. L , 2002 Hsp90 as a and S. W. L , 1995 Role of the chaperone protein capacitor of phenotypic variation. Nature 417: 618–624. 1 Hsp104 in propagation of the yeast prion-like factor ½PSI . Sci- Rutherford, S. L., and S. Lindquist, 1998 Hsp90 as a capacitor for ence 268: 880–884. ooper itler ashikar aynes ill morphological evolution. Nature 396: 336–342. C , A. A., A. D. G ,A.C ,C.M.H ,K.J.H Sanchez, Y., and S. Lindquist, 1990 HSP104 required for induced et al., 2006 Alpha-synuclein blocks ER-Golgi traffic and Rab1 thermotolerance. Science 248: 1112–1115. rescues neuron loss in Parkinson’s models. Science 313(5785): Sanchez, Y., J. Taulien,K.A.Borkovich and S. Lindquist, 324–328. ai hitesell ogers indquist 1992 Hsp104 is required for tolerance to many forms of stress. D , C., L. W ,A.B.R and S. L , 2007 Heat- EMBO J. 11: 2357–2364. shock factor 1 is a powerful multifaceted modifier of carcinogen- Sangster, T. A., S. Lindquist and C. Queitsch, 2004 Under cover: esis. Cell 130: 1005–1018. ellavalle etersen indquist causes, effects and implications of Hsp90-mediated genetic ca- D , R., R. P and S. L , 1994 Preferential pacitance. BioEssays 26: 348–362. deadenylation of hsp70 mRNA plays a key role in regulating Sangster,T.A.,N.Salathia,H.N.Lee,E.Watanabe,K.Schellenberg hsp70 expression in Drosophila melanogaster. Mol. Cell. Biol. 14: et al., 2008a HSP90-buffered genetic variation is common in Arabi- 3646–3659. i omenico ugaisky indquist dopsis thaliana. Proc. Natl. Acad. Sci. USA 105(8): 2969–2974. D D , B. J., G. B and S. L. L , 1982 Heat Sangster,T.A.,N.Salathia,S.Undurraga,K.Schellenberg, shock and recovery are mediated by different translational mech- S. Lindquist et al., 2008b HSP90 affects the expression of genetic anisms. Proc. Natl. Acad. Sci. USA 78: 3531–3535. uennwald agadish uchowski indquist variation and developmental stability in quantitative traits. Proc. D , M. L., S. J ,P.J.M and S. L , Natl. Acad. Sci. USA 105(8): 2963–2968. 2006a Flanking sequences profoundly alter polyglutamine tox- Serio, T. R., A. G. Cashikar,A.S.Kowal,G.J.Sawicki,J.J.Moslehi icity in yeast. Proc. Natl. Acad. Sci. USA 103(29): 11045–11050. et al., 2000 Nucleated conformational conversion and the rep- Duennwald, M. L., S. Jagadish,F.Giorgini,P.J.Muchowski and S. indquist lication of conformational information by a prion determinant. L , 2006b A network of protein interactions deter- Science 289: 1317–1321. mines polyglutamine toxicity. Proc. Natl. Acad. Sci. USA 103(29): Si, K., S. Lindquist and E. R. Kandel, 2003 A neuronal isoform 11051–11056. lover indquist of the Aplysia CPEB has prion-like properties. Cell 115: 879– G , J. R., and S. L , 1998 Hsp104, Hsp70 and Hsp40: a 891. novel chaperone system that rescues previously aggregated pro- Tessier, P. M., and S. Lindquist, 2007 Prion recognition elements teins. Cell 94: 73–82. lover owal chirmer atino iu govern nucleation, strain specificity and species barriers. Nature G , J. R., A. S. K ,E.C.S ,M.M.P , J.-J. L 447(7144): 556–561. et al., 1997 Self-seeded fibers formed by Sup35, the protein de- True, H. L., and S. L. Lindquist, 2000 A yeast prion provides an 1 terminant of ½PSI , a heritable prion-like factor of Saccharomyces exploratory mechanism for genetic variation and phenotypic di- cerevisiae. Cell 89: 811–819. olic indquist versity. Nature 407: 477–483. G , K., and S. L , 1989 The FLP recombinase of yeast True, H., I. Berlin and S. Lindquist, 2004 Epigenetic regulation of catalyzes site-specific recombination in the Drosophila genome. translation reveals hidden genetic variation to produce complex Cell 59: 499–509. traits. Nature 431: 184–187. Golic, M. M., Y. S. Rong,R.B.Petersen,S.L.Lindquist and K. G. elazquez i omenico indquist olic V , J. M., B. J. D D and S. L. L , G , 1997 FLP-mediated DNA mobilization to specific target 1980 Intracellular localization of heat shock proteins in Dro- sites in Drosophila chromosomes. Nucleic Acids Res. 25: 3665– sophila. Cell 20: 679–689. 3671. ogel arsell indquist rishnan indquist V , J. L., D. A. P and S. L , 1995 The heat-shock K , R., and S. L , 2005 Structural insights into a proteins hsp104 and hsp70 reactivate mRNA splicing after heat- yeast prion illuminate nucleation and strain diversity. Nature inactivation. Curr. Biol. 5: 306–317. 435: 765–772. ang indquist robitsch indquist W , Z., and S. L , 1998 Developmentally regulated nu- K , S., and S. L , 2000 Aggregation of huntingtin clear transport of transcription factors in Drosophila embryos en- in yeast varies with the length of the polyglutamine expansion ables the shock response. Development 125: 4841–4850. and the expression of chaperone proteins. Proc. Natl. Acad. Welte, M. A., J. M. Tetrault,R.P.Dellavalle and S. L. Lindquist, Sci. USA 97: 1589–1594. indquist 1993 A new method for manipulating transgenes: engineering L , S. L., 1980 Varying patterns of protein synthesis during heat tolerance in a complex multicellular organism. Curr. Biol. 3: heat shock: implications for regulation. Dev. Biol. 77: 463–479. indquist 842–853. L , S. L., 1981 Regulation of protein synthesis during heat Xu, Y., and S. Lindquist, 1993 Heat-shock protein hsp90 governs shock. Nature 293: 311–314. v-src c enzie eselson the activity of pp60 kinase. Proc. Natl. Acad. Sci. USA 90: M K , S. L., and M. M , 1977 Translation of heat- 7074–7078. induced messenger RNA in vitro. J. Mol. Biol. 117: 279–283. u inger indquist c enzie enikoff eselson X , Y., M. S and S. L , 1999 Maturation of the tyrosine M K , S. L., S. H and M. M , 1975 Localization kinase c-src as a kinase and as a substrate depends on the molecular of RNA from heat-induced polysomes at puff sites in Drosophila chaperone Hsp90. Proc. Natl. Acad. Sci. USA 96: 109–114. melanogaster. Proc. Natl. Acad. Sci. USA 72: 1117–1121. Yost, J. G., and S. L. Lindquist, 1986 RNA splicing is interrupted by Mukhopadhyay, S., R. Krishnan,E.A.Lemke,S.Lindquist and A. eniz heat shock and rescued by synthesis. Cell 45: A. D , 2007 A natively unfolded yeast prion monomer 185–193. adopts an ensemble of collapsed and rapidly fluctuating struc- Yost, H. J., and S. L. Lindquist, 1988 Translation of unspliced tran- tures. Proc. Natl. Acad. Sci. USA. 104(8): 2649–2654. uteiro indquist scripts after heat shock. Science 242: 1544–1548. O , T. F., and S. L , 2003 Yeast cells provide insight Yost, H. J., and S. Lindquist, 1991 Heat shock proteins affect RNA into alpha-synuclein biology and pathobiology. Science 302: processing during the heat shock response of Saccharomyces cere- 1772–1775. visiae. Mol. Cell. Biol. 11: 1062–1068. Parsell, D., A. Kowal,M.A.Singer and S. Lindquist, 1994 Pro- tein disaggregation mediated by heat-shock protein HSP104. Nature 372: 475–478. NANCY HOPKINS