Institute of Biochemistry II │ Goethe University Medical Faculty, Frankfurt

Ubiquitin and Ubiquitin-like protein modification systems control a wide variety of cellular key processes. Our laboratory is studying mechanistic and functional aspects of the Ubiquitin-like SUMO system in mammalian cells. SUMO (Small Ubiquitin-like Modifier) functions as a post-translational modifier that is covalently attached to lysine residues of target proteins. Human cells express three SUMO forms, which are conjugated in a pathway that requires the E1 activating enzyme Aos1/Uba2, the E2 conjugating enzyme Ubc9 and in many cases involves E3 SUMO ligases.
SUMO modification is a dynamic, reversible process, in which the demodification of a given SUMO-conjugate is catalyzed by SUMO-specific proteases of the SENP family.
SUMO conjugation/deconjugation typically modulates protein-protein interactions thereby controlling cellular key pathways, including gene expression programs, ribosome biogenesis, mitotic progression or genomic integrity.
Signaling by SUMO generally relies on the recognition of a modified protein by a binding partner that contains a specialized SUMO binding module termed SUMO interaction motif (SIM).
However, a detailed understanding of SUMO function in most pathways is still incomplete because the relevant targets of modification and the corresponding SUMO-dependent binding partners have not been identified. In our work we therefore want to pinpoint the critical targets of SUMO in selected cellular pathways and aim to understand the dynamics of SUMO/SIM interactions.

Prof. Dr. Stefan Müller

+49 (0) 69 6301-83647

Stefan Müller studied pharmacy at Ludwig Maximilians University in Munich before moving into life science research. After graduating, and following his genuine interest in molecular mechanisms underlying pharmacological and physiological effects, he abandoned the classical career path of a pharmacist. Instead, he took a deep dive into basic science and pursued a PhD in biochemical endocrinology at University Hospital Hamburg-Eppendorf. Stefan first came across SUMO during his postdoctoral studies in the group of Anne Dejean at Pasteur Institute in Paris. Ever since, the molecule that he himself once dubbed as ‘ubiquitin’s mysterious cousin’, dominated his scientific interest. In 2001, he returned to Germany to start his first independent group at the Max Planck Institute of Biochemistry (Munich-Martinsried) in the Department of Stefan Jentsch, before accepting a professorship at the Institute of Biochemistry II (IBC2) of Goethe University Frankfurt in 2011. Since 2016, Stefan is also the acting managing director of the Gustav Embden Center for Biological Chemistry, of which IBC2 forms an integral part. Stefan is dedicated to delivering highest quality of student education. He is responsible for teaching curricula in biochemistry at the medical faculty and is leading the Frankfurt Summer School for Medical Students. Stefan investigates post-translational regulation mechanisms in mammalian cells and their impact on nuclear organization, gene expression programs and ribosome biogenesis. His general focus is on the small ubiquitin related modifier (SUMO) system, which plays a major regulatory role in these processes. As a postdoc with Anne Dejean, he was the first to discover that SUMO determines the organization of PML nuclear bodies and the degradation of the oncogenic fusion protein PML-RARα in response to the anti-leukemogenic drug arsenic. Over the past decade, his team played a major role in revealing how the dynamics of SUMO conjugation and deconjugation shapes multiprotein complexes involved in ribosome biogenesis and epigenetic regulation. A main focus of his research is on dissecting the mechanisms of SUMO-mediated protein-protein interactions. His group has elucidated how SUMO recognition domains in target proteins interact with SUMO, thereby controlling cellular signaling pathways. He revealed the regulatory roles for phosphorylation and for acetylation in this process, adding a next layer of complexity in SUMO network control.

Anna-Kira Löffert

Gina Gotthardt

Gina Gotthardt studied Biochemistry (B. Sc. and M. Sc) at the Goethe University Frankfurt and obtained her degree in 2021. In her Master´s thesis she studied the role of ZC3H14 in mRNA export and nuclear splicing surveillance. In December 2021, Gina started to do her PhD in the lab of Stefan Müller at the IBC2 in Frankfurt to characterize and target RNF4 functions in tumors, using PROTAC technology.

Hannah Mende

+49 (0) 69 6301-4785

Hannah Mende studied Molecular Biology (B. Sc.) and Biomedicine (M. Sc.) at the JGU in Mainz and obtained her degree in 2017. In her Master´s thesis she studied RNAs associated to extracellular vesicles and the involvement of RNA binding proteins in RNA sorting mechanisms. In July 2017 she joined Stefan Müller´s group at the IBCII in Frankfurt to study the involvement of SUMOylation in autophagy within the SFB 1177.

Jan Keiten-Schmitz

+49 (0) 69 6301-6698

Jan Keiten-Schmitz was born in Freiburg, Germany. He studied Biology in Darmstadt and Heidelberg and obtained his diploma degree in 2013. In his diploma thesis he studied the TOM complex of Leishmania tarentolae. In September 2013 he started his PhD in the lab of Stefan Müller at the IBCII. Jan is studying the SUMO-targeted E3 ubiquitin-protein ligases (STUbLs) RNF4 and RNF111.

Judith Dönig

+49 (0) 69 6301-4785

Judith Dönig was born in Frankfurt and studied Biosciences (B.Sc.) and Molecular Biosciences (M.Sc) at the Goethe-University in Frankfurt. In her master thesis she studied the alanine- and formate- metabolism of the acetogenic bacterium Acetobacterium woodii. She has been part of the Müller group as a PhD student since April 2019 and focusses on the characterization of the SUMO-specific isopeptidase SENP5.

Kristina Wagner

+49 (0) 69 6301-5569

Dr. Luca Mendler

+49 (0) 69 6301-5820

Luca Mendler was born in Baja, Hungary. She studied medicine at the University of Szeged, Hungary and obtained her diploma in 1997. During her PhD she analyzed the molecular regulation of skeletal muscle regeneration at the University of Szeged as well as the Catholic University of Leuven, Belgium. After completing her PhD thesis in 2000, she kept on working on the molecular mechanisms regulating skeletal and cardiac muscle growth in the Institute of Biochemistry, Szeged (2000-2004). As an assistant professor she was teaching biochemistry for Hungarian, English and German medical students for several years as well (2004-2014). In 2008-2009 she received a scholarship of the Max Planck Society for deciphering the cell-autonomous role of the growth regulator myostatin in the heart in the Max-Planck-Insitute for Heart- and Lung Research, Bad Nauheim, Germany. In 2014 she joined to the Institute of Biochemistry II at the Goethe University, Frankfurt and has been involved in various teaching activities for medical students. She also started to work in the group of Stefan Müller analyzing the role of SUMO modification in the heart, more specifically, the possible function&redox regulation of SUMOylation during cardiac ischemia/reperfusion injury.

Paul Hotz

+49 (0) 69 6301-4785

Paul grew up in Essen and graduated from school in Wiesbaden with general qualification for university entrance (Abitur). He studied medicine at Goethe-Universität Frankfurt am Main and obtained the 1.Staatsexamen in summer 2017. Since September 2017 he started his MD Thesis in the SUMO signalling Group of Stefan Müller at Institute of Biochemestry II. He is now focussing on the role of SUMO system during cardiac ischemia/reperfusion injury and the identification of novel SUMO targets via mass spectrometry.

Tabea Stark

+49 (0) 69 6301-4785

Dr. Upayan Patra

+49 (0) 69 6301-6298

Upayan completed his Ph.D. in the field of molecular virology in 2021 from Indian Council of Medical Research-National Institute of Cholera and Enteric Diseases (ICMR-NICED), Kolkata, India. His doctoral research work revolved around dissecting host-virus interactions on high throughput platforms to yield targets and pathways which are either beneficial or detrimental to viral propagation and therefore subject to therapeutic interventions. He moved to Frankfurt in 2021 to join the Müller lab for pursuing post-doctoral research in SUMO signaling under various pathological settings.

Past Members:

Kathrin Schunck (Geb. Kunz)

Linda Röder

Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity.
Shin D, Mukherjee R, Grewe D, Bojkova D, Baek K, Bhattacharya A, Schulz L, Widera M, Mehdipour AR, Tascher G, Geurink PP, Wilhelm A, van der Heden van Noort GJ, Ovaa H, Müller S, Knobeloch KP, Rajalingam K, Schulman BA, Cinatl J, Hummer G, Ciesek S, Dikic I.
Nature. 2020 Nov;587(7835):657-662. doi: 10.1038/s41586-020-2601-5. Epub 2020 Jul 29.
PMID: 32726803 Link

Vitamin K antagonism impairs the bone marrow microenvironment and hematopoiesis.
Verma D, Kumar R, Pereira RS, Karantanou C, Zanetti C, Minciacchi VR, Fulzele K, Kunz K, Hoelper S, Zia-Chahabi S, Jabagi MJ, Emmerich J, Dray-Spira R, Kuhlee F, Hackmann K, Schroeck E, Wenzel P, Müller S, Filmann N, Fontenay M, Pajevic PD, Krause DS.Blood. 2019 Jul 18;134(3):227-238. doi: 10.1182/blood.2018874214. Epub 2019 Apr 19.PMID: 31003999 Free PMC article. Link

Full length RTN3 regulates turnover of tubular endoplasmic reticulum via selective autophagy.
Grumati P, Morozzi G, Hölper S, Mari M, Harwardt MI, Yan R, Müller S, Reggiori F, Heilemann M, Dikic I.Elife. 2017 Jun 15;6:e25555. doi: 10.7554/eLife.25555.PMID: 28617241 Link

Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase activity and gene expression regulator.
Jung J, Nayak A, Schaeffer V, Starzetz T, Kirsch AK, Müller S, Dikic I, Mittelbronn M, Behrends C.Elife. 2017 Feb 14;6:e23063. doi: 10.7554/eLife.23063.PMID: 28195531 Link

Inhibition of MLL1 histone methyltransferase brings the developmental clock back to naïve pluripotency.
Muller S, Nayak A.Stem Cell Investig. 2016 Oct 20;3:58. doi: 10.21037/sci.2016.09.14. eCollection 2016.PMID: 27868040 Link

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Signaling by SUMO relies on the recognition of the post-translational mark by specialized interaction modules termed SUMO interaction motifs (SIMs). SUMO-mediated protein/protein interactions are frequently mediated by the non-covalent binding of SUMO conjugates to SIMs in a binding partner.
A common key determinant of SIMs is a core of hydrophobic amino acids. In a subset of SIM-containing proteins, including members of the PIAS (Protein inhibitor of activated STAT) family, this hydrophobic core is flanked by serine residues and a stretch of acidic residues. By using PIAS1 as a SUMO-binding model protein we could previously show that these serine residues are phosphorylated by the kinase CK2 and could demonstrate that this dictates binding of free SUMO and SUMO conjugates to PIAS1 (Stehmeier and Muller, 2009).
CK2-regulated phosphoSIM modules were also dissected in the tumor suppressor PML and the exosome component PMSCL1, indicating that these modules serve as general platforms that integrate CK2- and SUMO-regulated signaling networks. The characterization of SIMs in PIAS and PML revealed a new regulatory layer for SUMO recognition by SIM modules. One aspect of our current project is to functionally characterize the phosphoSIM modules of PIAS family members.
Moreover, we aim to elucidate other mechanisms that regulate the dynamics of SUMO/SIM interactions and want to understand how this affects specific cellular pathways, in particular PIAS-mediated transcriptional processes.

Stehmeier, P. & Muller, S. (2009). Phospho-regulated SUMO interaction modules connect the SUMO system to CK2 signaling. Mol. Cell 33, 400-409.

Ribosome biogenesis is a tightly controlled pathway that requires an intricate spatial and temporal interplay of protein networks. Most structural rRNA components are generated in the nucleolus and assembled into pre-ribosomal particles, which are transferred for further maturation to the nucleoplasm and cytoplasm. In mammalian cells, however, it is largely unclear what drives these processes.
Our previous and current work revealed a critical role for the SUMO-specific protease SENP3 in the control of nucleolar dynamics and ribosome biogenesis. In particular, we could show that SENP3 is critically involved in the maturation of the 28S rRNA and the nucleolar export of the 60S pre-ribosomal subunit (Haindl et al., 2008, Finkbeiner et al., 2011). We now identified and characterized a novel SENP3-associated complex comprised of PELP1, TEX10 and WDR18 and demonstrate that this complex is involved in maturation and nucleolar release of the large ribosomal subunit. We identified PELP1 and as a SENP3-sensitive targets of SUMO2 and provide evidence that the SUMO system determines the nucleolar partitioning of the PELP1-TEX10-WDR18 complex.
This work thus defines the PELP1-TEX10-WDR18 complex as a novel regulator of ribosome biogenesis and suggests that its SUMO-regulated distribution provides a mechanism to coordinate the rate of ribosome formation. We propose a model where the balanced SUMO conjugation/deconjugation controls the dynamic association of this complex with 60S pre-ribosomal particles. We now aim to get mechanistic insights how sumoylation/desumoylation processes mediate the dynamics of pre-60S pre-ribosomal particles. Moreover, we want to understand how the SUMO system coordinates the rate of ribosome formation with the physiological state of the cell.

Haindl, M., Harasim, T., Eick, D. & Muller, S. (2008). The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing. EMBO Rep. 9, 273-279.
Finkbeiner, E., Haindl, M. & Muller S. (2011) The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex. EMBO J., 30, 1067 – 1078.

Institute of Biochemistry II
University Hospital Frankfurt
Goethe University
Theodor-Stern-Kai 7 / Building 75
60590 Frankfurt am Main
Germany

Tel (office): +49 (0) 69 6301 83647
Tel (lab): +49 (0) 69 6301 5569
Fax: +49 (0) 69 6301 5577

stefan.mueller@biochem2.de

All IBCII Members Contact Data

SUMO Signaling

Prof. Dr. Stefan Müller

Anna-Kira Löffert

Gina Gotthardt

Hannah Mende

Jan Keiten-Schmitz

Judith Dönig

Kristina Wagner

Dr. Luca Mendler

Paul Hotz

Tabea Stark

Dr. Upayan Patra

Past Members:

Kathrin Schunck (Geb. Kunz)

Linda Röder

Mechanistic and functional aspects of SUMO-SIM interactions

The SUMO system in mammalian ribosome biogenesis