Mark Hochstrasser, PhD
Research & Publications
Biography
News
Research Summary
We wish to understand at a molecular level how specific eukaryotic
proteins are selected for rapid degradation even while most proteins
are spared. Such turnover occurs primarily through the
ubiquitin-proteasome system and is central to a variety of cell
regulatory mechanisms, many of medical relevance including many cancers. The proteasome is a
molecular machine that fragments proteins into short peptides. More
generally, we study the reversible enzymatic coupling of proteins to
other proteins within cells. The prototypical example of such a protein
modifier is ubiquitin, but at least a dozen such systems exist. While
ubiquitin is commonly used to mark its targets for destruction, the
consequences of protein ligation to the various “ubiquitin-like
proteins” are less understood. One such protein that we study, SUMO, is
attached to many proteins and is crucial for cell-cycle progression.
Much of our work is conducted in baker’s yeast, a model organism ideal
for genetic and biochemical analysis, but we also use human tissue culture cells and Drosophila in certain studies. We also study endosymbiotic bacteria that live in eukaryotic cellsand often manipulate their hosts by causing changes to the ubiquitin system.
Speciailzed Terms: Ubiquitin; Proteasome; SUMO; Saccharomyces cerevisiae; Drosophila melanogaster; Protein Degradation; Wolbachia; Cytoplasmic Incompatibility
Extensive Research Description
Our lab has as its general focus one of the fundamental regulatory systems of eukaryotic cells – the ubiquitin system. Ubiquitin and an array of related molecules (ubiquitin-like proteins or Ubls) such as SUMO are small, highly conserved proteins that are covalently attached to other intracellular proteins, resulting in various functional alterations of these targets. The ubiquitin system has only recently come under close scrutiny, and an extraordinary array of cell regulatory functions is gradually being uncovered. Moreover, many links are now being found between defects in this pathway and human disease, including many cancers, developmental abnormalities, Parkinson’s disease, Alzheimer’s disease, and certain severe forms of mental retardation.
The research in our laboratory can be grouped into three broad and overlapping areas. First, we wish to understand, at a mechanistic and molecular level, how specific proteins are rapidly degraded within eukaryotic cells while most proteins are spared. Such turnover is central to a great variety of regulatory mechanisms, including many of medical relevance. Much of this regulated degradation occurs via the highly conserved ubiquitin-proteasome system. We are currently studying a transmembrane ubiquitin ligase that resides in the nuclear envelope and endoplasmic reticulum. This ligase attaches ubiquitin to both nuclear regulatory proteins and to misfolded membrane proteins degraded at the ER (ER-associated degradation or ERAD). The proteasome is a large, cylindrical machine that fragments proteins into short peptides. Our primary current interest with the proteasome is its mechanism of assembly.
In our second major area of research, we are analyzing the function and dynamics of protein modification by other Ubls. The prototypical example of a protein that is covalently attached to other proteins is ubiquitin, but in recent years, evidence for at least a dozen such systems has come to light. While ubiquitin generally is used to mark its targets for destruction, the consequences of protein ligation to the various Ubls are often poorly understood. The Ubl called SUMO is attached to many proteins in vivo and is crucial for cell-cycle progression. We discovered the first enzymes that can remove SUMO from other proteins, causing this protein modification to be highly dynamic. We are trying to understand the functional consequences of SUMO-protein modification, particularly in the cell cycle and chromatin-mediate gene transcription, and to determine the basis of specificity for the SUMO-cleaving proteases. Much of our work is conducted in the yeast Saccharomyces cerevisiae, an organism that permits both facile genetic manipulation and detailed biochemical analysis.
A third, more recent research focus has been on endosymbiotic bacteria that manipulate their eukaryotic hosts by secreting enzymes, including ubiquitin-specific proteases, into the host cell cytoplasm. Wolbachia bacteria alter host processes in ways that increase bacterial inheritance by transmission through the female germline. One such mechanism is called cytoplasmic incompatibility (CI), which has important applications in mosquito-vectored human disease control; we recently discovered the proteins responsible for CI. We also study an unusual ubiquitin protease from Orientia tsutsugamushi, an endosymbiont that causes the mite-vectored disease scrub typhus.
Coauthors
Research Interests
Biochemistry; Drosophila; Enzymes; Genetics; Molecular Biology; Saccharomyces cerevisiae; Transcription Factors; Microscopy, Immunoelectron; Wolbachia; Ubiquitin; Proteasome Endopeptidase Complex; Cell Growth Processes; Mutant Chimeric Proteins; Sumoylation
Public Health Interests
Mosquito-borne Diseases
Selected Publications
- Species-specific protein-protein interactions govern the humanization of the 20S proteasome in yeast.Sultana S, Abdullah M, Li J, Hochstrasser M, Kachroo A. Species-specific protein-protein interactions govern the humanization of the 20S proteasome in yeast. Genetics 2023 PMID: 37364278, DOI: 10.1093/genetics/iyad117.
- Molecular Biology of Cytoplasmic Incompatibility Caused by Wolbachia EndosymbiontsHochstrasser M. Molecular Biology of Cytoplasmic Incompatibility Caused by Wolbachia Endosymbionts Annual Review Of Microbiology 2023, 77 PMID: 37285552, DOI: 10.1146/annurev-micro-041020-024616.
- Proteasomes: Isolation and Activity AssaysLi Y, Tomko R, Hochstrasser M. Proteasomes: Isolation and Activity Assays Current Protocols 2023, 3: e717. PMID: 37026813, DOI: 10.1002/cpz1.717.
- Ectopic RING activity at the ER membrane differentially impacts ERAD protein quality control pathwaysMehrtash A, Hochstrasser M. Ectopic RING activity at the ER membrane differentially impacts ERAD protein quality control pathways Journal Of Biological Chemistry 2023, 299: 102927. PMID: 36682496, PMCID: PMC9950527, DOI: 10.1016/j.jbc.2023.102927.
- Orientia tsutsugamushi OtDUB Is Expressed and Interacts with Adaptor Protein Complexes during InfectionAdcox H, Berk J, Hochstrasser M, Carlyon J. Orientia tsutsugamushi OtDUB Is Expressed and Interacts with Adaptor Protein Complexes during Infection Infection And Immunity 2022, 90: e00469-22. PMID: 36374099, PMCID: PMC9753657, DOI: 10.1128/iai.00469-22.
- Elements of the ERAD ubiquitin ligase Doa10 regulating sequential poly-ubiquitylation of its targetsMehrtash A, Hochstrasser M. Elements of the ERAD ubiquitin ligase Doa10 regulating sequential poly-ubiquitylation of its targets IScience 2022, 25: 105351. PMID: 36325070, PMCID: PMC9619350, DOI: 10.1016/j.isci.2022.105351.
- The Relationship between ER Stress and Protein Quality Control at the TransloconBroshar C, Buchanan B, Mehrtash A, Runnebohm A, Snow B, Scanameo L, Hochstrasser M, Rubenstein E. The Relationship between ER Stress and Protein Quality Control at the Translocon The FASEB Journal 2020, 34: 1-1. DOI: 10.1096/fasebj.2020.34.s1.00497.
- Site-Specific Cation Release Drives Actin Filament Severing by Vertebrate CofilinKang H, Bradley M, Cao W, Zhou K, Grintsevich E, Michelot A, Reisler E, Sindelar C, Hochstrasser M, De La Cruz E. Site-Specific Cation Release Drives Actin Filament Severing by Vertebrate Cofilin Biophysical Journal 2015, 108: 24a-25a. DOI: 10.1016/j.bpj.2014.11.159.
- A second degradation signal within the short‐lived transcription factor MATalpha2 (937.1)Hickey C, Hochstrasser M. A second degradation signal within the short‐lived transcription factor MATalpha2 (937.1) The FASEB Journal 2014, 28 DOI: 10.1096/fasebj.28.1_supplement.937.1.
- Actin Filament Severing by Vertebrate Cofilin is Driven by Linked Cation ReleaseKang H, Bradley M, McCullough B, Grintsevich E, Michelot A, Hochstrasser M, Reisler E, De La Cruz E. Actin Filament Severing by Vertebrate Cofilin is Driven by Linked Cation Release Biophysical Journal 2014, 106: 164a-165a. DOI: 10.1016/j.bpj.2013.11.938.
- Chapter 462 The Doa4 Deubiquitylating Enzyme (Saccharomyces cerevisiae)Amerik A, Hochstrasser M. Chapter 462 The Doa4 Deubiquitylating Enzyme (Saccharomyces cerevisiae) 2013, 2049-2052. DOI: 10.1016/b978-0-12-382219-2.00461-0.
- Chapter 528 Ulp2 SUMO ProteaseGillies J, Su D, Hochstrasser M. Chapter 528 Ulp2 SUMO Protease 2013, 2362-2365. DOI: 10.1016/b978-0-12-382219-2.00526-3.
- Chapter 161 The Ubiquitin–Proteasome SystemHochstrasser M. Chapter 161 The Ubiquitin–Proteasome System 2010, 1293-1296. DOI: 10.1016/b978-0-12-374145-5.00161-3.
- Ubiquitin and Ubiquitin‐like Protein ConjugationHochstrasser M. Ubiquitin and Ubiquitin‐like Protein Conjugation 2008, 249-278. DOI: 10.1002/9783527610754.mr02.
- An emerging role for thioester‐linked polyubiquitin chains in protein degradationRavid T, Hochstrasser M. An emerging role for thioester‐linked polyubiquitin chains in protein degradation The FASEB Journal 2008, 22: 605.7-605.7. DOI: 10.1096/fasebj.22.1_supplement.605.7.
- Biochemical Functions of Ubiquitin and Ubiquitin‐like Protein ConjugationHochstrasser M. Biochemical Functions of Ubiquitin and Ubiquitin‐like Protein Conjugation 2007, 249-278. DOI: 10.1002/9783527619320.ch11a.
- SUMO and ubiquitin transactions at the ER and nuclear envelopeHochstrasser M, Lewis A, Felberbaum R, Deng M. SUMO and ubiquitin transactions at the ER and nuclear envelope 2007, 2007 DOI: 10.1240/sav_gbm_2007_h_002065.
- Biochemical Functions of Ubiquitin and Ubiquitin‐like Protein ConjugationHochstrasser M. Biochemical Functions of Ubiquitin and Ubiquitin‐like Protein Conjugation 2005, 249-278. DOI: 10.1002/9783527620210.ch11.
- Chapter 181 The Ubiquitin-Proteasome SystemHochstrasser M. Chapter 181 The Ubiquitin-Proteasome System 2003, 347-350. DOI: 10.1016/b978-012124546-7/50542-8.
- SP-RING for SUMO New Functions Bloom for a Ubiquitin-like ProteinHochstrasser M. SP-RING for SUMO New Functions Bloom for a Ubiquitin-like Protein Cell 2001, 107: 5-8. PMID: 11595179, DOI: 10.1016/s0092-8674(01)00519-0.
- Unraveling the means to the end in ATP-dependent proteasesHochstrasser M, Wang J. Unraveling the means to the end in ATP-dependent proteases Nature Structural & Molecular Biology 2001, 8: 294-296. PMID: 11276243, DOI: 10.1038/86153.
- The Doa4 Deubiquitinating Enzyme Is Functionally Linked to the Vacuolar Protein-sorting and Endocytic PathwaysAmerik A, Nowak J, Swaminathan S, Hochstrasser M. The Doa4 Deubiquitinating Enzyme Is Functionally Linked to the Vacuolar Protein-sorting and Endocytic Pathways Molecular Biology Of The Cell 2000, 11: 3365-3380. PMID: 11029042, PMCID: PMC14998, DOI: 10.1091/mbc.11.10.3365.
- Evolution and function of ubiquitin-like protein-conjugation systemsHochstrasser M. Evolution and function of ubiquitin-like protein-conjugation systems Nature Cell Biology 2000, 2: e153-e157. PMID: 10934491, DOI: 10.1038/35019643.
- Biochemistry. All in the ubiquitin family.Hochstrasser M. Biochemistry. All in the ubiquitin family. Science 2000, 289: 563-4. PMID: 10939967, DOI: 10.1126/science.289.5479.563.
- A viable ubiquitin‐activating enzyme mutant for evaluating ubiquitin system function in Saccharomyces cerevisiaeSwanson R, Hochstrasser M. A viable ubiquitin‐activating enzyme mutant for evaluating ubiquitin system function in Saccharomyces cerevisiae FEBS Letters 2000, 477: 193-198. PMID: 10908719, DOI: 10.1016/s0014-5793(00)01802-0.
- The Yeast ULP2 (SMT4) Gene Encodes a Novel Protease Specific for the Ubiquitin-Like Smt3 ProteinLi S, Hochstrasser M. The Yeast ULP2 (SMT4) Gene Encodes a Novel Protease Specific for the Ubiquitin-Like Smt3 Protein Molecular And Cellular Biology 2000, 20: 2367-2377. PMID: 10713161, PMCID: PMC85410, DOI: 10.1128/mcb.20.7.2367-2377.2000.
- The Doa4 Deubiquitinating Enzyme Is Required for Ubiquitin Homeostasis in YeastSwaminathan S, Amerik A, Hochstrasser M. The Doa4 Deubiquitinating Enzyme Is Required for Ubiquitin Homeostasis in Yeast Molecular Biology Of The Cell 1999, 10: 2583-2594. PMID: 10436014, PMCID: PMC25490, DOI: 10.1091/mbc.10.8.2583.
- Eukaryotic 20S proteasome catalytic subunit propeptides prevent active site inactivation by N‐terminal acetylation and promote particle assemblyArendt C, Hochstrasser M. Eukaryotic 20S proteasome catalytic subunit propeptides prevent active site inactivation by N‐terminal acetylation and promote particle assembly The EMBO Journal 1999, 18: 3575-3585. PMID: 10393174, PMCID: PMC1171436, DOI: 10.1093/emboj/18.13.3575.
- Substrate Targeting in the Ubiquitin SystemLaney J, Hochstrasser M. Substrate Targeting in the Ubiquitin System Cell 1999, 97: 427-430. PMID: 10338206, DOI: 10.1016/s0092-8674(00)80752-7.
- Structure and functional analyses of the 26S proteasome subunits from plants – Plant 26S proteasomeFu H, Girod P, Doelling J, van Nocker S, Hochstrasser M, Finley D, Vierstra R. Structure and functional analyses of the 26S proteasome subunits from plants – Plant 26S proteasome Molecular Biology Reports 1999, 26: 137-146. PMID: 10363660, DOI: 10.1023/a:1006926322501.
- A new protease required for cell-cycle progression in yeastLi S, Hochstrasser M. A new protease required for cell-cycle progression in yeast Nature 1999, 398: 246-251. PMID: 10094048, DOI: 10.1038/18457.
- Interaction of the Doa4 Deubiquitinating Enzyme with the Yeast 26S ProteasomePapa F, Amerik A, Hochstrasser M. Interaction of the Doa4 Deubiquitinating Enzyme with the Yeast 26S Proteasome Molecular Biology Of The Cell 1999, 10: 741-756. PMID: 10069815, PMCID: PMC25199, DOI: 10.1091/mbc.10.3.741.
- A Deubiquitinating Enzyme That Disassembles Free Polyubiquitin Chains Is Required for Development but Not Growth in Dictyostelium *Lindsey D, Amerik A, Deery W, Bishop J, Hochstrasser M, Gomer R. A Deubiquitinating Enzyme That Disassembles Free Polyubiquitin Chains Is Required for Development but Not Growth in Dictyostelium * Journal Of Biological Chemistry 1998, 273: 29178-29187. PMID: 9786928, DOI: 10.1074/jbc.273.44.29178.
- Degradation Signal Masking by Heterodimerization of MATα2 and MATa1 Blocks Their Mutual Destruction by the Ubiquitin-Proteasome PathwayJohnson P, Swanson R, Rakhilina L, Hochstrasser M. Degradation Signal Masking by Heterodimerization of MATα2 and MATa1 Blocks Their Mutual Destruction by the Ubiquitin-Proteasome Pathway Cell 1998, 94: 217-227. PMID: 9695950, DOI: 10.1016/s0092-8674(00)81421-x.
- Unified nomenclature for subunits of the Saccharomyces cerevisiae proteasome regulatory particleFinley D, Tanaka K, Mann C, Feldmann H, Hochstrasser M, Vierstra R, Johnston S, Hampton R, Haber J, McCusker J, Silver P, Frontali L, Thorsness P, Varshavsky A, Byers B, Madura K, Reed S, Wolf D, Jentsch S, Sommer T, Baumeister W, Goldberg A, Fried V, Rubin D, Glickman M, Toh-e A. Unified nomenclature for subunits of the Saccharomyces cerevisiae proteasome regulatory particle Trends In Biochemical Sciences 1998, 23: 244-245. PMID: 9697412, DOI: 10.1016/s0968-0004(98)01222-5.
- Molecular Organization of the 20S Proteasome Gene Family from Arabidopsis thalianaFu H, Doelling J, Arendt C, Hochstrasser M, Vierstra R. Molecular Organization of the 20S Proteasome Gene Family from Arabidopsis thaliana Genetics 1998, 149: 677-692. PMID: 9611183, PMCID: PMC1460176, DOI: 10.1093/genetics/149.2.677.
- An Evolutionarily Conserved Gene on Human Chromosome 5q33–q34,UBH1,Encodes a Novel Deubiquitinating EnzymeHansen-Hagge T, Janssen J, Hameister H, Papa F, Zechner U, Seriu T, Jauch A, Becke D, Hochstrasser M, Bartram C. An Evolutionarily Conserved Gene on Human Chromosome 5q33–q34,UBH1,Encodes a Novel Deubiquitinating Enzyme Genomics 1998, 49: 411-418. PMID: 9615226, DOI: 10.1006/geno.1998.5275.
- There’s the Rub: a novel ubiquitin-like modification linked to cell cycle regulationHochstrasser M. There’s the Rub: a novel ubiquitin-like modification linked to cell cycle regulation Genes & Development 1998, 12: 901-907. PMID: 9531529, DOI: 10.1101/gad.12.7.901.
- The Deubiquitinating EnzymesWilkinson K, Hochstrasser M. The Deubiquitinating Enzymes 1998, 99-125. DOI: 10.1007/978-1-4899-1922-9_4.
- Ubiquitin-Dependent Degradation of Transcription RegulatorsHochstrasser M, Kornitzer D. Ubiquitin-Dependent Degradation of Transcription Regulators 1998, 279-302. DOI: 10.1007/978-1-4899-1922-9_9.
- SUMO-1: Ubiquitin gains weightJohnson P, Hochstrasser M. SUMO-1: Ubiquitin gains weight Trends In Cell Biology 1997, 7: 408-413. PMID: 17708991, DOI: 10.1016/s0962-8924(97)01132-x.
- In vivo disassembly of free polyubiquitin chains by yeast Ubp14 modulates rates of protein degradation by the proteasomeAmerik A, Swaminathan S, Krantz B, Wilkinson K, Hochstrasser M. In vivo disassembly of free polyubiquitin chains by yeast Ubp14 modulates rates of protein degradation by the proteasome The EMBO Journal 1997, 16: 4826-4838. PMID: 9305625, PMCID: PMC1170118, DOI: 10.1093/emboj/16.16.4826.
- Identification of the yeast 20S proteasome catalytic centers and subunit interactions required for active-site formationArendt C, Hochstrasser M. Identification of the yeast 20S proteasome catalytic centers and subunit interactions required for active-site formation Proceedings Of The National Academy Of Sciences Of The United States Of America 1997, 94: 7156-7161. PMID: 9207060, PMCID: PMC23776, DOI: 10.1073/pnas.94.14.7156.
- UBIQUITIN-DEPENDENT PROTEIN DEGRADATIONHochstrasser M. UBIQUITIN-DEPENDENT PROTEIN DEGRADATION Annual Review Of Genetics 1996, 30: 405-439. PMID: 8982460, DOI: 10.1146/annurev.genet.30.1.405.
- Autocatalytic Subunit Processing Couples Active Site Formation in the 20S Proteasome to Completion of AssemblyChen P, Hochstrasser M. Autocatalytic Subunit Processing Couples Active Site Formation in the 20S Proteasome to Completion of Assembly Cell 1996, 86: 961-972. PMID: 8808631, DOI: 10.1016/s0092-8674(00)80171-3.
- Protein Degradation or Regulation: Ub the JudgeHochstrasser M. Protein Degradation or Regulation: Ub the Judge Cell 1996, 84: 813-815. PMID: 8601303, DOI: 10.1016/s0092-8674(00)81058-2.
- Degradation of the MATα2 transcriptional regulator is mediated by the proteasomeRichter-Ruoff B, Wolf D, Hochstrasser M. Degradation of the MATα2 transcriptional regulator is mediated by the proteasome FEBS Letters 1995, 358: 104-104. DOI: 10.1016/0014-5793(95)90822-f.
- Ubiquitin, proteasomes, and the regulation of intracellular protein degradationHochstrasser M. Ubiquitin, proteasomes, and the regulation of intracellular protein degradation Current Opinion In Cell Biology 1995, 7: 215-223. PMID: 7612274, DOI: 10.1016/0955-0674(95)80031-x.
- Degradation of the yeast MATα2 transcriptional regulator is mediated by the proteasomeRichter-Ruoff B, Wolf D, Hochstrasser M. Degradation of the yeast MATα2 transcriptional regulator is mediated by the proteasome FEBS Letters 1994, 354: 50-52. PMID: 7957900, DOI: 10.1016/0014-5793(94)01085-4.
- The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product of the human tre-2 oncogenePapa F, Hochstrasser M. The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product of the human tre-2 oncogene Nature 1993, 366: 313-319. PMID: 8247125, DOI: 10.1038/366313a0.
- Editorial overviewHinnebusch A, Hochstrasser M. Editorial overview Current Opinion In Cell Biology 1993, 5: 941-943. DOI: 10.1016/0955-0674(93)90073-y.
- Multiple ubiquitin-conjugating enzymes participate in the in vivo degradation of the yeast MATα2 repressorChen P, Johnson P, Sommer T, Jentsch S, Hochstrasser M. Multiple ubiquitin-conjugating enzymes participate in the in vivo degradation of the yeast MATα2 repressor Cell 1993, 74: 357-369. PMID: 8393731, DOI: 10.1016/0092-8674(93)90426-q.
- Ubiquitin and intracellular protein degradationHochstrasser M. Ubiquitin and intracellular protein degradation Current Opinion In Cell Biology 1992, 4: 1024-1031. PMID: 1336669, DOI: 10.1016/0955-0674(92)90135-y.
- Functions of Intracellular Protein Degradation in YeastHochstrasser M. Functions of Intracellular Protein Degradation in Yeast 1991, 307-329. DOI: 10.1007/978-1-4615-3760-1_14.
- Functions of Intracellular Protein Degradation in YeastHochstrasser M. Functions of Intracellular Protein Degradation in Yeast 1991, 13: 307-329. PMID: 1369338, DOI: 10.1007/978-1-4615-3760-1_14.
- In vivo degradation of a transcriptional regulator: The yeast α2 repressorHochstrasser M, Varshavsky A. In vivo degradation of a transcriptional regulator: The yeast α2 repressor Cell 1990, 61: 697-708. PMID: 2111732, DOI: 10.1016/0092-8674(90)90481-s.
- Chromosome structure in four wild-type polytene tissues of Drosophila melanogasterHochstrasser M. Chromosome structure in four wild-type polytene tissues of Drosophila melanogaster Chromosoma 1987, 95: 197-208. PMID: 3111801, DOI: 10.1007/bf00330351.
- Light microscope based analysis of three‐dimensional structure: Applications to the study of Drosophila salivary gland nuclei. I. Data collection and analysisMathog D, Hochstrasser M, Sedat J. Light microscope based analysis of three‐dimensional structure: Applications to the study of Drosophila salivary gland nuclei. I. Data collection and analysis Journal Of Microscopy 1985, 137: 241-252. PMID: 3999131, DOI: 10.1111/j.1365-2818.1985.tb02582.x.
- Characteristic folding pattern of polytene chromosomes in Drosophila salivary gland nucleiMathog D, Hochstrasser M, Gruenbaum Y, Saumweber H, Sedat J. Characteristic folding pattern of polytene chromosomes in Drosophila salivary gland nuclei Nature 1984, 308: 414-421. PMID: 6424026, DOI: 10.1038/308414a0.
- Properties of the T4 bacteriophage DNA replication apparatus: The T4 dda DNA helicase is required to pass a bound RNA polymerase moleculeBedinger P, Hochstrasser M, Jongeneel C, Alberts B. Properties of the T4 bacteriophage DNA replication apparatus: The T4 dda DNA helicase is required to pass a bound RNA polymerase molecule Cell 1983, 34: 115-123. PMID: 6136341, DOI: 10.1016/0092-8674(83)90141-1.