Stefan Jentsch (1955–2016)

Stefan Jentsch, whose unusual creativity and trailblazing work changed forever the fields of ubiquitin biology, DNA repair, splicing, and autophagy, sadly passed away in Munich on October 29 after a short and severe illness. Stefan was born in Berlin on May 29, 1955. Following his school and university years, Stefan embarked on his graduate thesis in his still-divided hometown and joined Thomas Trautner’s group at the Max Planck Institute of Molecular Genetics. His dissertation work on DNA modifications by methyltransferases, completed in 1983, focused on one of his life-long scientific passions: the intricate crosstalk between DNA and proteins. On the hunt for the ‘‘gold mines of cell biology,’’ as he would call it, the freshly minted PhD moved to Boston, where he joined Alex Varshavsky’s lab at the Massachusetts Institute of Technology. In the exciting years to follow, Stefan and his colleagues identified key players of the ubiquitin pathway and thus laid the foundation for our current understanding of how this essential modification is being implemented in cells. Bucking the trend in a genetics laboratory, Stefan chose a biochemical approach to purify enzymes of the ubiquitin cascade, and a few 150-l fermenters later, he managed to track down the first E2 ubiquitin-conjugating enzyme. As this was decades before the emergence of streamlined protein identification bymass spectrometry, Stefan subjected the key band of his purification gel to good old Edman sequencing, and right after obtaining his coveted result, he raced to call his postdoc advisor Varshavsky. Only then did he realize that it was 4:00 in the morning. Stefan’s excitement was justified, as the first E2 enzyme turned out to be RAD6, which immediately linked the DNA repair and ubiquitin fields. Already at the forefront of a budding field, Stefan moved back to Germany, where the Max Planck Society had convinced the rising star to accept a group leader position in their Friedrich Miescher Laboratory in Tübingen. There, Stefan set out to use yeast genetics to discover new E2 enzymes and cellular functions for the ubiquitin pathway. One of these projects led to the realization that unfolded proteins of the endoplasmic reticulum are returned to the cytoplasm for ubiquitylation and degradation, a pathway that has become known as ERassociated degradation, or ERAD. ERAD protects cells from the accumulation of unfolded secretory or membrane proteins, and interference with this process likely contributes to the therapeutic benefits of the proteasome inhibitors that have revolutionized the outlook for myeloma and leukemia patients. For this fundamental work, Stefan received the Gottfried Wilhelm Leibniz Prize, the highest recognition awarded by the German Science Foundation. Moving up through the ranks of academia, Stefan left Tübingen for Heidelberg, where he became a professor at the Center for Molecular Biology. One of his hallmark contributions of this time was the insight that ubiquitin chain formation can occur in distinct initiation and elongation steps, with the latter being catalyzed by an enzyme they coined E4. His findings did not remain unnoticed, and in 1998, Stefan moved back to the Max Planck Society, this time joining the Institute of Biochemistry in Martinsried near Munich as one of its directors. He spent the longest time of his career there and left a strong mark at this institute; indeed, his taste for classic Bauhaus architecture and Le Corbusier and Breuer furniture is on display for everyone walking through the halls of his former workplace. In Martinsried, Stefan continued to recruit the most talented students and postdocs, but now, he was also able to support young group leaders, giving them a head start into the German academic system. The atmosphere in his lab was truly unique, and many longlasting friendships have their roots in these formative years of being a student in Stefan’s group. To many of us, one of our most cherished friendships was that with Stefan. During the Martinsried years, Stefan’s lab made several seminal discoveries. To name but a few, they revealed proteasomal cleavage as a mechanism to activate, rather than inhibit, membranebound transcription factors. This work led them to discover that p97/CDC48, a protein mutated in neurodegenerative diseases, acts as a ‘‘segregase’’ that takes apart protein complexes in a ubiquitin-dependent manner. They found roles for ubiquitin-like proteins, including NEDD8, which they showed to modify and regulate the large family of CULLIN-RING ligases, or HUB1, which controls alternative splicing without being attached to target proteins. Recently, they had identified receptors for ubiquitindependent autophagy in yeast, a pathway that had been well-studied in higher eukaryotes but had evaded recognition in yeast, and they isolated the essential players of a DNA repair pathway that detects covalent adducts between DNA and proteins. One of Stefan’s major findings in Martinsried, acknowledged with a LouisJeantet Prize, led him back to his scientific roots. While searching for proteins decorated with the ubiquitin cousin SUMO, Stefan and his team circled in on the DNA polymerase processivity factor PCNA. During their analysis of cells exposed to DNA damage, they noticed that some modified species of PCNA were not lost upon mutation of the SUMOylation enzymes. Stefan immediately suspected that the recalcitrant gel bands were ubiquitylated forms of PCNA, ultimately allowing his lab to Stefan Jentsch