Dieter Wolf (1941–2023): a life dedicated to understanding protein quality control and the ubiquitin‐proteasome system

Abstract

Obituary5 May 2023free access Dieter Wolf (1941–2023): a life dedicated to understanding protein quality control and the ubiquitin-proteasome system Alexander Varshavsky Alexander Varshavsky Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA Search for more papers by this author Daniel Finley Daniel Finley Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA Search for more papers by this author Alfred L Goldberg Alfred L Goldberg Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA Deceased Search for more papers by this author Tom A Rapoport Tom A Rapoport orcid.org/0000-0001-9911-4216 Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA Search for more papers by this author Thorsten Pfirrmann Corresponding Author Thorsten Pfirrmann [email protected] orcid.org/0000-0002-9474-9535 Department of Medicine, Health and Medical University, Potsdam, Germany Search for more papers by this author Alexander Varshavsky Alexander Varshavsky Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA Search for more papers by this author Daniel Finley Daniel Finley Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA Search for more papers by this author Alfred L Goldberg Alfred L Goldberg Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA Deceased Search for more papers by this author Tom A Rapoport Tom A Rapoport orcid.org/0000-0001-9911-4216 Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA Search for more papers by this author Thorsten Pfirrmann Corresponding Author Thorsten Pfirrmann [email protected] orcid.org/0000-0002-9474-9535 Department of Medicine, Health and Medical University, Potsdam, Germany Search for more papers by this author Author Information Alexander Varshavsky1, Daniel Finley2, Alfred L Goldberg2, Tom A Rapoport2 and Thorsten Pfirrmann *,3 1Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA 2Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA 3Department of Medicine, Health and Medical University, Potsdam, Germany *Corresponding author. E-mail: [email protected] The EMBO Journal (2023)e114222https://doi.org/10.15252/embj.2023114222 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Professor Dieter H. Wolf, a scientist of vision and depth, a role model for his students and colleagues, and a long-standing member of the Editorial Advisory Board of The EMBO Journal, sadly passed away on February 16th, 2023, in Stuttgart-Vaihingen, Germany. Dieter Wolf was born in Frankfurt am Main, Germany, on September 18th, 1941. Between 1962 and 1963, he studied engineering at the Technical University (TU) in Karlsruhe, where he later took up chemistry, and finished his studies at the Technical University (TUM) in Munich. At that time, Dieter became particularly interested in biochemistry and began his first (doctoral) investigations, on the regulation of E. coli glutamine synthetase, in the laboratory of Prof. Dr. Helmut Holzer at the University of Freiburg. During his subsequent postdoctoral studies, he worked in the laboratory of Prof. Gerald Fink at Cornell University in Ithaca, New York. While there, Dieter pioneered the use of yeast as a model organism to study intracellular protein degradation. He then returned to Freiburg, joining the biochemistry faculty in 1975. In 1989, Dieter was appointed as a full Professor of Biochemistry (as well as the chair and director of the Institute of Biochemistry) at the University of Stuttgart, where he stayed until his retirement in 2011. Over several decades, Dieter focused on S. cerevisiae as a model eukaryote. Using yeast, he combined genetics and biochemistry, often in highly original ways, to make fundamental discoveries about regulated protein degradation. Already in 1975, he isolated the first yeast mutant that was directly relevant to intracellular protein degradation (Wolf & Fink, 1975), a pioneering advance at a time when understanding of intracellular proteolysis was just beginning to emerge. During the next decade, discoveries by Dieter and his coworkers encompassed several novel yeast proteases, including the alpha-factor-processing endoprotease Kex2 (yscF) (Achstetter & Wolf, 1985) and, most notably, the protease yscE (Achstetter et al, 1984), which was subsequently found to be a component of the yeast proteasome (Heinemeyer et al, 1991). This proteolytic nanomachine, as Dieter liked to call the proteasome, turned out to be the long-sought but initially elusive protease that plays a central role in regulated and selective protein degradation in all eukaryotes. With this discovery, the last step in ubiquitin-mediated proteolysis was clarified, and the overall pathway is now referred to as the ubiquitin-proteasome system (UPS) (Heinemeyer et al, 1991). In retrospect, the initial work on the proteasome component yscE and subsequent studies of the proteasome by the Wolf laboratory played a major role in our understanding of pathways through which cells selectively eliminate misfolded or otherwise abnormal proteins and also destroy protein regulators that evolved to be conditionally short-lived (Kostova & Wolf, 2003). Protein aggregation and other forms of protein damage are a major cause of many human diseases, including neurodegenerative syndromes and cancers, and have been implicated in aging as well. Over the last decades, both fundamental and clinically oriented studies of the UPS have become major areas of biomedical research. In another groundbreaking advance, the Wolf laboratory (contemporaneously with the laboratory of Prof. Jeffrey Brodsky) showed that a misfolded glycosylated protein in the lumen of the endoplasmic reticulum (ER) can be detected by “sensors” in the ER and, astonishingly, get transported back to the cytosol for its subsequent degradation by the UPS (Hiller et al, 1996). The process of transporting previously ER-imported proteins back into the cytosol was termed ER-associated degradation or ERAD. A second foundational advance in the field came from highly successful genetic screens to identify ERAD components, carried out by the laboratories of Dieter Wolf and Randy Hampton. In subsequent years, the Wolf laboratory contributed many results to our understanding of the ERAD process. ERAD is now a large and medically important field, in part because some human birth defects, causative for diseases such as cystic fibrosis, involve mutations in proteins that fail to mature in the ER and therefore become targeted for destruction via ERAD. Dieter also discovered that, in yeast, several major enzymes of the gluconeogenesis pathway, including fructose-1,6-bisphosphatase, are selectively and conditionally destroyed in response to high glucose levels (Schork et al, 1994). These and other studies by Dieter and coworkers led to the discovery of the evolutionarily conserved multisubunit GID (glucose-induced degradation) complex, a specific ubiquitin ligase that drives these events (Santt et al, 2008). The resulting GID-mediated proteolytic system, later termed the Pro/N-degron pathway and recently implicated in a variety of stress responses, has become a dynamic and rapidly growing field. In 2007, the prestigious prize “Landesforschungspreis of Baden-Württemberg” (Germany) recognized Dieter's contributions to this and other fields. Dieter was not only a brilliant researcher, but also a great mentor, a kind, perceptive, and enthusiastic teacher whose knowledge of UPS and related fields was nothing short of encyclopedic. His desk was frequently covered with stacks of scientific papers that sometimes reached precarious heights, but he knew precisely where specific papers could be found among these stacks! Biology students at the University of Stuttgart greatly respected Dieter not only as a scientist, but also as a tough but fair examiner, who guided students planning to study at other universities in Germany and abroad. He cared deeply about and supported both local and international scientific collaborations. His laboratory welcomed a number of young scientists from all over the world. Dieter also organized the now legendary annual and highly successful Söllerhaus science meetings at a picturesque retreat in the Alps. These meetings, famous for their warm atmosphere, often sparked highly productive collaborations. Dieter Wolf was an outstanding scientist, a caring and most helpful mentor to his students, and a great friend to colleagues all over the world. He will be sorely missed. Legend/Picture credits: Dieter H. Wolf (1941–2023) (second from left) celebrating his 65th birthday together with his colleagues Prof. Matthias Müller, Prof. Phil Coffino, and Prof. Aaron Ciechanover (left to right)/Archive material from the Institute of Biochemistry, University of Stuttgart, used with permission. References Achstetter T, Wolf DH (1985) Hormone processing and membrane-bound proteinases in yeast. EMBO J 4: 173–177Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Achstetter T, Ehmann C, Osaki A, Wolf DH (1984) Proteolysis in eukaryotic cells. Proteinase yscE, a new yeast peptidase. J Biol Chem 259: 13344–13348CrossrefCASPubMedWeb of Science®Google Scholar Heinemeyer W, Kleinschmidt JA, Saidowsky J, Escher C, Wolf DH (1991) Proteinase yscE, the yeast proteasome/multicatalytic-multifunctional proteinase: mutants unravel its function in stress induced proteolysis and uncover its necessity for cell survival. EMBO J 10: 555–562Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Hiller MM, Finger A, Schweiger M, Wolf DH (1996) ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science 273: 1725–1728CrossrefCASPubMedWeb of Science®Google Scholar Kostova Z, Wolf DH (2003) For whom the bell tolls: protein quality control of the endoplasmic reticulum and the ubiquitin-proteasome connection. EMBO J 22: 2309–2317Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Santt O, Pfirrmann T, Braun B, Juretschke J, Kimmig P, Scheel H, Hofmann K, Thumm M, Wolf DH (2008) The yeast GID complex, a novel ubiquitin ligase (E3) involved in the regulation of carbohydrate metabolism. Mol Biol Cell 19: 3323–3333CrossrefCASPubMedWeb of Science®Google Scholar Schork SM, Bee G, Thumm M, Wolf DH (1994) Site of catabolite inactivation. Nature 369: 283–284CrossrefCASPubMedWeb of Science®Google Scholar Wolf DH, Fink GR (1975) Proteinase C (carboxypeptidase Y) mutant of yeast. J Bacteriol 123: 1150–1156CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 0,Issue 0,This cover highlights the article Shuffled ATG8 interacting motifs form an ancestral bridge between UFMylation and autophagy by Lorenzo Picchianti, Victor Sanchez de Medina Hernandez, Ni Zhan, Yasin Dagdas and colleagues. 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