About

Mark Hochstrasser, PhD, is the Eugene Higgins Professor of Molecular Biophysics and Biochemistry at Yale University, with additional appointments in the Department of Molecular, Cellular and Developmental Biology, the Yale Cancer Center, and the Yale Biological and Biomedical Sciences Program. He has been part of the Yale faculty since 2000. His educational background includes a B.A. from Rutgers University, a Ph.D. from the University of California, San Francisco, and postdoctoral research at the Massachusetts Institute of Technology. Hochstrasser has received numerous honors, such as a Young Investigator Award from the Cancer Research Foundation, and has been recognized as a Searle Scholar and Fletcher Scholar. He is an elected Fellow of the American Academy of Arts and Sciences, the American Association for the Advancement of Science, and the Connecticut Academy of Science and Engineering. His work has been published in prominent scientific journals including Nature, Cell, and the Proceedings of the National Academy of Sciences, and he has served on editorial boards and NIH study sections. His research focuses on the ubiquitin system, a fundamental regulatory mechanism in eukaryotic cells, exploring how proteins are targeted for degradation via the ubiquitin-proteasome system, the function and dynamics of protein modification by ubiquitin-like proteins such as SUMO, and the manipulation of host processes by endosymbiotic bacteria like Wolbachia and Orientia tsutsugamushi. His laboratory investigates the molecular mechanisms underlying these processes, with implications for understanding human diseases such as cancer, neurodegenerative disorders, and developmental abnormalities.

Research topics

• Cell biology
• Biology
• Genetics
• Computer Science
• Chemistry
• Biochemistry
• Virology
• Microbiology
• Computational biology

Selected publications

• A cut above: Bacterial deubiquitinases with ubiquitin clippase activity

  Molecular Cell · 2025-03-01 · 1 citations

  articleOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Deubiquitylases and nucleases in bacterial symbiont-induced cytoplasmic incompatibility

  Biochemical Society Transactions · 2025-10-01 · 2 citations

  articleOpen accessSenior author

  In myriad arthropod species, maternally transmitted symbiotic bacteria spread through populations by manipulating host reproduction, most frequently by a mechanism called cytoplasmic incompatibility (CI). CI occurs when bacterially infected males fertilize uninfected females, typically causing paternal chromatin condensation and segregation defects and usually embryonic arrest in the first zygotic cell cycle. Embryos survive if the female is similarly infected, which promotes bacterial spread. The endosymbiont best known for CI is Wolbachia, now widely used against mosquitoes that vector viral diseases such as dengue fever. Although CI is induced by Wolbachia resident in testes, mature sperm carry no bacteria, indicating they alter sperm in a way that, following fertilization, interferes with embryogenesis. CI-inducing factors (Cifs) are expressed from syntenic Wolbachia cifA-cifB genes. CifB is required in the male germline to induce CI, while CifA expression in the host female is sufficient to rescue viability. Importantly, CifA suppresses lethality through its binding to CifB. Different CifB proteins have distinct CI-relevant enzymatic functions, in particular, deubiquitylase and nuclease activities. Consistent with these genetic data, CifB is packaged into sperm during spermiogenesis. While sperm morphological disruption has been observed in fruit flies carrying cif transgenes, a causal role in CI is unclear. Also not understood is how maternally provisioned CifA rescues embryo viability. Exciting new findings with diverse symbiotic bacteria reveal cifA-cifB-like operons on extrachromosomal plasmids. These results suggest far wider deployment of Wolbachia-related CI factors than previously thought and multiple mechanisms for lateral cif gene transfer.

  PublisherOA PDFDOI

• Auto-sumoylation of the yeast Ubc9 E2 SUMO-conjugating enzyme extends cellular lifespan

  Nature Communications · 2025-04-20 · 5 citations

  articleOpen access

  Calorie restriction (CR) provides anti-aging benefits through diverse processes, such as reduced metabolism and growth and increased mitochondrial activity. Although controversy still exists regarding CR-mediated lifespan effects, many researchers are seeking interventions that mimic the effects of CR. Yeast has proven to be a useful model system for aging studies, including CR effects. We report here that yeast adapted through in vitro evolution to the severe cellular stress caused by loss of the Ulp2 SUMO-specific protease exhibit both enhanced growth rates and replicative lifespan, and they have altered gene expression profiles similar to those observed in CR. Notably, in certain evolved ulp2Δ lines, an increase in the auto-sumoylation of Ubc9 E2 SUMO-conjugating enzyme results in altered regulation of multiple targets involved in energy metabolism and translation at both transcriptional and post-translational levels. This increase is essential for the survival of aged cells and CR-mediated lifespan extension. Thus, we suggest that high Ubc9 auto-sumoylation exerts potent anti-aging effects by promoting efficient energy metabolism-driven improvements in cell replication abilities. This potential could be therapeutically explored for the development of promising CR-mimetic strategies.

  PublisherOA PDFDOI

• Use of a High-Affinity Ubiquitin-Binding Domain to Detect and Purify Ubiquitinated Substrates and Their Interacting Proteins

  BIO-PROTOCOL · 2025-01-01

  articleOpen accessSenior author

  . The following protocol describes a step-by-step process for the enrichment of ubiquitinated proteins from baker's yeast and mammalian cell lysates using OtUBD. The OtUBD affinity resin can strongly enrich both mono- and poly-ubiquitinated proteins from crude lysates. The protocol further describes the use of different buffer formulations to specifically enrich for proteins covalently modified by ubiquitin with or without proteins that associate with them. Combining different OtUBD-mediated enrichment protocols with liquid chromatography-tandem mass spectrometry (LC-MS/MS) helps distinguish the pool of covalently ubiquitinated proteins (the ubiquitinome) from ubiquitin- or ubiquitinated protein-interacting proteins (the ubiquitin interactome). The OtUBD tool described in the protocol has been used successfully with downstream applications such as immunoblotting and differential proteomics. It provides researchers with a versatile and economical tool for the study of ubiquitin biology. Key Features • The protocol offers a native workflow and a denaturing workflow for enrichment of ubiquitinated proteins with or without noncovalently associated proteins, respectively. • Included in the protocol are different resin compositions, lysate preparation methods, elution methods, and pulldown formats to suit different experimental needs. • The protocol has been used in various applications, including immunoblotting, proteomics, and UbiCREST (ubiquitin chain restriction), and works with all types of ubiquitin conjugates. • The protocol was developed and tested with budding yeast and mammalian cell lysates but can be adapted to other biological samples and organisms.

  PublisherDOI

• AMPK alters proteasome phosphorylation status and prevents persistent proteasome condensates

  Genetics · 2025-08-29 · 1 citations

  articleSenior author

  Proteasomes are large multiprotein complexes required for selective intracellular protein degradation, regulating numerous cellular processes and maintaining protein homeostasis and organismal health. In the budding yeast Saccharomyces cerevisiae grown under different glucose conditions, proteasomes undergo dynamic phase transitions between free and condensate states concomitant with nucleocytoplasmic translocation. Low glucose-induced cytoplasmic proteasome condensates are usually reversible but become persistent in the absence of AMP-activated protein kinase (AMPK). AMPK is important for proteasome condensate dissolution and proteasome nuclear reimport upon glucose refeeding of quiescent cells. Here we found that AMPK activities and the AMPK signaling pathway affect proteasome subunit phosphorylation, which correlates with the solubility and reversibility of proteasome condensates. Nuclear and cytoplasmic AMPK isoforms function redundantly in proteasome condensate dissolution. AMPK interacts with the proteasome regulatory particle in an AMPK activity-independent manner. At least 50 kinases and phosphatases have been found to associate with the AMPK complex. Therefore, the prevention of persistent proteasome condensate formation by AMPK likely results from regulating the antagonistic effects of downstream kinases and phosphatases on proteasome phosphorylation. A mechanistic understanding of the downstream effector proteins of AMPK that directly regulate proteasome subunit phosphorylation will provide insights into how proteasome phosphorylation is linked to proteasome condensate regulation.

  PublisherDOI

• AMPK alters proteasome phosphorylation status and prevents persistent proteasome condensates

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-02

  preprintOpen accessSenior authorCorresponding

  Abstract Proteasomes are large multiprotein complexes required for selective intracellular protein degradation, regulating numerous cellular processes and maintaining protein homeostasis and organismal health. In the budding yeast Saccharomyces cerevisiae grown under different glucose conditions, proteasomes undergo dynamic phase transitions between free and condensate states concomitant with nucleocytoplasmic translocation. Low glucose-induced cytoplasmic proteasome condensates are usually reversible but become persistent in the absence of AMP-activated protein kinase (AMPK). AMPK is important for proteasome condensate dissolution and proteasome nuclear reimport upon glucose refeeding of quiescent cells. Here we found that AMPK activities and the AMPK signaling pathway affect proteasome subunit phosphorylation, which correlates with the solubility and reversibility of proteasome condensates. Nuclear and cytoplasmic AMPK functions redundantly in proteasome condensate dissolution. AMPK interacts with the proteasome regulatory particle in an AMPK activity-independent manner. At least 50 kinases and phosphatases have been found to associate with the AMPK complex. Therefore, the prevention of persistent proteasome condensate formation by AMPK likely results from regulating the antagonistic effects of downstream kinases and phosphatases on proteasome phosphorylation. A mechanistic understanding of the downstream effector proteins of AMPK that directly regulate proteasome subunit phosphorylation will provide insights into how proteasome phosphorylation is linked to proteasome condensate regulation. Article summary Proteasomes undergo dynamic nucleocytoplasmic translocation and phase transitions in response to glucose starvation. AMP-activated protein kinase (AMPK) is important for cytoplasmic proteasome condensate dissolution and proteasome nuclear reentry in budding yeast cells upon glucose refeeding of quiescent cells. This study demonstrates that AMPK interacts with proteasomes, and the AMPK pathway regulates proteasome phosphorylation status and condensate solubility during reversible proteasome condensate formation. AMPK and the PP1 phosphatase dynamically regulate phosphorylation of multiple proteasome subunits. Therefore, the regulation of proteasome phosphorylation by AMPK is likely to be central to proteasome biomolecular condensate formation and dissolution.

  PublisherOA PDFDOI

• Sumoylation of cyclin and its therapeutic potential for cancer

  Animal Cells and Systems · 2025-12-06

  articleOpen accessSenior authorCorresponding

  The precision of the cell cycle is essential for organismal development, tissue homeostasis, and the prevention of malignancies. Cyclins and cyclin-dependent kinases (CDKs) play pivotal roles in regulating cell cycle progression. Recent studies have underscored the importance of post-translational modifications, particularly sumoylation, in modulating the functions of cyclins. Sumoylation profoundly influences the stability, localization, and activity of cyclins D and E, which are crucial for the G1/S transition and DNA replication. Dysregulation of these processes is a hallmark of various cancers, where aberrant sumoylation enhances the oncogenic potential of cyclins. This review examines how sumoylation governs cyclin dynamics, maintains cell division fidelity, and contributes to cancer progression. Moreover, advances in targeting the SUMO pathway offer new therapeutic opportunities for treating cyclin-related malignancies, positioning sumoylation-based strategies as promising tools in precision medicine. Gaining a deeper understanding of how sumoylation regulates cyclins may ultimately transform therapeutic approaches for cyclin-dependent diseases.

  PublisherDOI

• Auto-sumoylation of the Ubc9 E2 SUMO-conjugating Enzyme Extends Cellular Lifespan

  Research Square · 2024-03-21 · 1 citations

  preprintOpen accessSenior author
  PublisherOA PDFDOI

• Yeast 26S proteasome nuclear import is coupled to nucleus-specific degradation of the karyopherin adaptor protein Sts1

  Scientific Reports · 2024-01-24 · 4 citations

  articleOpen accessSenior author

  In eukaryotes, the ubiquitin-proteasome system is an essential pathway for protein degradation and cellular homeostasis. 26S proteasomes concentrate in the nucleus of budding yeast Saccharomyces cerevisiae due to the essential import adaptor protein Sts1 and the karyopherin-α protein Srp1. Here, we show that Sts1 facilitates proteasome nuclear import by recruiting proteasomes to the karyopherin-α/β heterodimer. Following nuclear transport, the karyopherin proteins are likely separated from Sts1 through interaction with RanGTP in the nucleus. RanGTP-induced release of Sts1 from the karyopherin proteins initiates Sts1 proteasomal degradation in vitro. Sts1 undergoes karyopherin-mediated nuclear import in the absence of proteasome interaction, but Sts1 degradation in vivo is only observed when proteasomes successfully localize to the nucleus. Sts1 appears to function as a proteasome import factor during exponential growth only, as it is not found in proteasome storage granules (PSGs) during prolonged glucose starvation, nor does it appear to contribute to the rapid nuclear reimport of proteasomes following glucose refeeding and PSG dissipation. We propose that Sts1 acts as a single-turnover proteasome nuclear import factor by recruiting karyopherins for transport and undergoing subsequent RanGTP-initiated ubiquitin-independent proteasomal degradation in the nucleus.

  PublisherOA PDFDOI

• Limiting 20S proteasome assembly leads to unbalanced nucleo-cytoplasmic distribution of 26S/30S proteasomes and chronic proteotoxicity

  iScience · 2024-10-04 · 3 citations

  articleOpen access

  -deficient cells accumulate in the nucleus where they degrade mitotic substrates, allowing cells to proceed through mitosis; however, these cells present cytoplasmic aggregates and constitutive activation of the heat shock response. Thus, our data suggest that an increase in proteasome assembly induced by folding stress functions as an additional layer to proteasome regulation and highlight the importance of balanced proteasome compartmentalization to sustain cell proliferation while maintaining proper cytoplasmic proteostasis.

  PublisherDOI

Recent grants

• Predoctoral Program in Cellular and Molecular Biology

  NIH · $45.7M · 1990–2020

• Function and Assembly of Eukaryotic Proteasomes

  NIH · $3.8M · 2008–2020

• Degradation of Short Lived Regulatory Protein in Yeast

  NIH · $3.6M · 1992–2019

• Degradation of Short Lived Regulatory Proteins

  NIH · $5.1M · 1992–2023

• Functions and Mechanisms of Deubiquitinating Enzymes

  NIH · $7.3M · 1996–2021

Frequent coauthors

• Robert J. Tomko

  Florida State University

  23 shared

• Stefan G. Kreft

  University of Konstanz

  20 shared

• Hong‐Yeoul Ryu

  Kyungpook National University

  19 shared

• M Funakoshi

  19 shared

• Tommer Ravid

  Hebrew University of Jerusalem

  17 shared

• Alexander Y. Amerik

  Institute of Biochemical Physics NM Emanuel

  16 shared

• Feroz R. Papa

  14 shared

• John F. Beckmann

  Auburn University

  14 shared

Labs

• Hochstrasser LabPI

  Former Members

Awards & honors

• Young Investigator Award from the Cancer Research Foundation
• Searle Scholar
• Fletcher Scholar
• Fellow of the American Academy of Arts and Sciences
• Fellow of the American Association for the Advancement of Sc…