Dr. Ruth Geiss-Friedlander

Research in my lab focuses on the function of proteases in different cellular pathways. Since reactions catalyzed by proteases are (mostly) non-reversible – proteolysis and limited proteolysis are tightly regulated processes. How do proteases identify their substrates? How is this process regulated? What are the molecular and cellular outcomes of the processing event? We combine biochemistry, structure-function analysis, interactome studies and cell biology to address these questions.

Two amino-dipeptidyl peptidases, DPP8 and DPP9 are a major research focus in my lab. DPP8 and DPP9 have the rare ability to hydrolyze a peptide bond post proline, and thus act as molecular switches. Amongst other we study the roles of DPP8 and DPP9 in DNA damage repair and in cell signaling, by targeting key proteins such as the tumor-suppressor BRCA2, and the tyrosine kinase Syk.

10 selected publications:

• Dipeptidyl peptidase 9 triggers BRCA2 degradation and promotes DNA damage repair.
  Bolgi O, Silva-Garcia M, Ross B, Pilla E, Kari V, Killisch M, Spitzner M, Stark N, Lenz C, Weiss K, Donzelli L, Gorrell MD, Grade M, Riemer J, Urlaub H, Dobbelstein M, Huber R, Geiss-Friedlander R. EMBO Rep. 2022 Oct 6;23(10):e54136
• Chemoproteomics-Enabled Identification of 4-Oxo-β-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.
  Carvalho LAR, Ross B, Fehr L, Bolgi O, Wöhrle S, Lum KM, Podlesainski D, Vieira AC, Kiefersauer R, Félix R, Rodrigues T, Lucas SD, Groß O, Geiss-Friedlander R, Cravatt BF, Huber R, Kaiser M, Moreira R.
  Angew Chem Int Ed Engl. 2022 Sep 11. DOI: 10.1002/anie.202210498
• Structures and mechanism of dipeptidyl peptidases 8 and 9, important players in cellular homeostasis and cancer.
  Ross B, Krapp S, Augustin M, Kierfersauer R, Arciniega M, Geiss-Friedlander R, Huber R.
  Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1437-E1445
• Hair cell synaptic dysfunction, auditory fatigue and thermal sensitivity in otoferlin Ile515Thr mutants.
  Strenzke N, Chakrabarti R, Al-Moyed H, Müller A, Hoch G, Pangrsic T, Yamanbaeva G, Lenz C, Pan KT, Auge E, Geiss-Friedlander R, Urlaub H, Brose N, Wichmann C, Reisinger E.
  EMBO J. 2016 Dec 1;35(23):2519-2535.
• DPP9 is a novel component of the N-end rule pathway targeting the tyrosine kinase Syk.
  Justa-Schuch D, Silva-Garcia M, Pilla E, Engelke M, Kilisch M, Lenz C, Möller U, Nakamura F, Urlaub H, Geiss-Friedlander R.
  Elife. 2016 Sep 10;5:e16370.
• Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation.
  Kunadt M, Eckermann K, Stuendl A, Gong J, Russo B, Strauss K, Rai S, Kügler S, Falomir Lockhart L, Schwalbe M, Krumova P, Oliveira LM, Bähr M, Möbius W, Levin J, Giese A, Kruse N, Mollenhauer B, Geiss-Friedlander R, Ludolph AC, Freischmidt A, Feiler MS, Danzer KM, Zweckstetter M, Jovin TM, Simons M, Weishaupt JH, Schneider A.
  Acta Neuropathol. 2015 May;129(5):695-713.
• The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus.
  Justa-Schuch D, Möller U, Geiss-Friedlander R.
  Cell Mol Life Sci. 2014 Sep;71(18):3611-26
• The cytoplasmic peptidase DPP9 is rate-limiting for degradation of proline-containing peptides.
  Geiss-Friedlander R, Parmentier N, Möller U, Urlaub H, Van den Eynde BJ, Melchior F.
  J Biol Chem. 2009 Oct 2;284(40):27211-9
• Concepts in sumoylation: a decade on.
  Geiss-Friedlander R, Melchior F.
  Nat Rev Mol Cell Biol. 2007, Dec;8(12):947-56
• A regulatory link between ER-associated protein degradation and the unfolded-protein response.
  Friedlander R, Jarosch E, Urban J, Volkwein C, Sommer T.
  Nat Cell Biol 2: 379-384. 2000