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.

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 6301-4785

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

Linda Röder

+49 (0) 69 6301-4785

Linda grew up in Brandenburg and later in Bavaria, where she completed an apprenticeship as chemical technician at the international chemical concern Wacker Chemie AG.
She then moved to Saxony and worked as a deputy shift leader in the integrated polysilicon production system.
In 2015, she moved to Hesse and graduated from the Hessenkolleg in Wiesbaden.
Subsequently, she began her studies in medicine at the Goethe University in Frankfurt/ Main.
In autumn 2019 she started her medical doctoral thesis in the SUMO Signaling Group of Prof. Dr. Stefan Müller at the Institute of Biochemistry II, where she focuses on the role of SUMO ligases in cellular signaling pathways, also with regard to the connections to neurodegenerative diseases.
On this occasion, signaling pathways in which stress-induced SUMOylation influences stress granule assembly and disassembly, are from particular interest.
The different ligases with their diverse tasks in cellular signaling pathways represent an interesting and promising therapeutic starting point for research into pathologically persistent stress granules such as those found in neurodegenerative diseases.

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)

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

Publications from PubMed: 56

Patra U, Müller S A Tale of Usurpation and Subversion: SUMO-Dependent Integrity of Promyelocytic Leukemia Nuclear Bodies at the Crossroad of Infection and Immunity. Front Cell Dev Biol 2021. 9 696234 Link

Keiten-Schmitz J, Röder L, Hornstein E, Müller-McNicoll M, Müller S SUMO: Glue or Solvent for Phase-Separated Ribonucleoprotein Complexes and Molecular Condensates? Front Mol Biosci 2021. 8 673038 Link

Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH, Abudu YP, Acevedo-Arozena A, Adamopoulos IE, Adeli K, Adolph TE, Adornetto A, Aflaki E, Agam G, Agarwal A, Aggarwal BB, Agnello M, Agostinis P, Agrewala JN, Agrotis A, Aguilar PV, Ahmad ST, Ahmed ZM, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy 2021. 17 (1) 1-382 Link

Hotz PW, Wiesnet M, Tascher G, Braun T, Müller S, Mendler L Profiling the Murine SUMO Proteome in Response to Cardiac Ischemia and Reperfusion Injury. Molecules 2020. 25 (23) Link

Keiten-Schmitz J, Wagner K, Piller T, Kaulich M, Alberti S, Müller S The Nuclear SUMO-Targeted Ubiquitin Quality Control Network Regulates the Dynamics of Cytoplasmic Stress Granules. Mol Cell 2020. 79 (1) 54-67.e7 Link

Biederstädt A, Hassan Z, Schneeweis C, Schick M, Schneider L, Muckenhuber A, Hong Y, Siegers G, Nilsson L, Wirth M, Dantes Z, Steiger K, Schunck K, Langston S, Lenhof HP, Coluccio A, Orben F, Slawska J, Scherger A, Saur D, Müller S, Rad R, Weichert W, Nilsson J, Reichert M, et al. SUMO pathway inhibition targets an aggressive pancreatic cancer subtype. Gut 2020. 69 (8) 1472-1482 Link

Keiten-Schmitz J, Schunck K, Müller S SUMO Chains Rule on Chromatin Occupancy. Front Cell Dev Biol 2019. 7 343 Link

Wagner K, Kunz K, Piller T, Tascher G, Hölper S, Stehmeier P, Keiten-Schmitz J, Schick M, Keller U, Müller S The SUMO Isopeptidase SENP6 Functions as a Rheostat of Chromatin Residency in Genome Maintenance and Chromosome Dynamics. Cell Rep 2019. 29 (2) 480-494.e5 Link

Kunz K, Müller S, Mendler L Assays of SUMO protease/isopeptidase activity and function in mammalian cells and tissues. Methods Enzymol 2019. 618 389-410 Link

Gärtner A, Wagner K, Hölper S, Kunz K, Rodriguez MS, Müller S Acetylation of SUMO2 at lysine 11 favors the formation of non-canonical SUMO chains. EMBO Rep 2018. 19 (11) Link

Kunz K, Piller T, Müller S SUMO-specific proteases and isopeptidases of the SENP family at a glance. J Cell Sci 2018. 131 (6) Link

Wiechmann S, Gärtner A, Kniss A, Stengl A, Behrends C, Rogov VV, Rodriguez MS, Dötsch V, Müller S, Ernst A Site-specific inhibition of the small ubiquitin-like modifier (SUMO)-conjugating enzyme Ubc9 selectively impairs SUMO chain formation. J Biol Chem 2017. 292 (37) 15340-15351 Link

Nayak A, Reck A, Morsczeck C, Müller S Flightless-I governs cell fate by recruiting the SUMO isopeptidase SENP3 to distinct genes. Epigenetics Chromatin 2017. 10 15 Link

Raman N, Weir E, Müller S The AAA ATPase MDN1 Acts as a SUMO-Targeted Regulator in Mammalian Pre-ribosome Remodeling. Mol Cell 2016. 64 (3) 607-615 Link

Husnjak K, Keiten-Schmitz J, Müller S Identification and Characterization of SUMO-SIM Interactions. Methods Mol Biol 2016. 1475 79-98 Link

Kunz K, Wagner K, Mendler L, Hölper S, Dehne N, Müller S SUMO Signaling by Hypoxic Inactivation of SUMO-Specific Isopeptidases. Cell Rep 2016. 16 (11) 3075-3086 Link

Mendler L, Braun T, Müller S The Ubiquitin-Like SUMO System and Heart Function: From Development to Disease. Circ Res 2016. 118 (1) 132-44 Link

Nayak A, Müller S SUMO-specific proteases/isopeptidases: SENPs and beyond. Genome Biol 2014. 15 (7) 422 Link

Raman N, Nayak A, Muller S mTOR signaling regulates nucleolar targeting of the SUMO-specific isopeptidase SENP3. Mol Cell Biol 2014. 34 (24) 4474-84 Link

Gärtner A, Muller S PML, SUMO, and RNF4: guardians of nuclear protein quality. Mol Cell 2014. 55 (1) 1-3 Link

Nayak A, Viale-Bouroncle S, Morsczeck C, Muller S The SUMO-specific isopeptidase SENP3 regulates MLL1/MLL2 methyltransferase complexes and controls osteogenic differentiation. Mol Cell 2014. 55 (1) 47-58 Link

Raman N, Nayak A, Muller S The SUMO system: a master organizer of nuclear protein assemblies. Chromosoma 2013. 122 (6) 475-85 Link

Ullmann R, Chien CD, Avantaggiati ML, Muller S An acetylation switch regulates SUMO-dependent protein interaction networks. Mol Cell 2012. 46 (6) 759-70 Link

Finkbeiner E, Haindl M, Raman N, Muller S SUMO routes ribosome maturation. Nucleus . 2 (6) 527-32 Link

van Wijk SJ, Müller S, Dikic I Shared and unique properties of ubiquitin and SUMO interaction networks in DNA repair. Genes Dev 2011. 25 (17) 1763-9 Link

Finkbeiner E, Haindl M, Muller S The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex. EMBO J 2011. 30 (6) 1067-78 Link

Jentsch S, Müller S Regulatory Functions of Ubiquitin and SUMO in DNA Repair Pathways. Subcell Biochem 2010. 54 184-94 Link

Messner S, Schuermann D, Altmeyer M, Kassner I, Schmidt D, Schär P, Müller S, Hottiger MO Sumoylation of poly(ADP-ribose) polymerase 1 inhibits its acetylation and restrains transcriptional coactivator function. FASEB J 2009. 23 (11) 3978-89 Link

Louria-Hayon I, Alsheich-Bartok O, Levav-Cohen Y, Silberman I, Berger M, Grossman T, Matentzoglu K, Jiang YH, Muller S, Scheffner M, Haupt S, Haupt Y E6AP promotes the degradation of the PML tumor suppressor. Cell Death Differ 2009. 16 (8) 1156-66 Link

Stehmeier P, Muller S Phospho-regulated SUMO interaction modules connect the SUMO system to CK2 signaling. Mol Cell 2009. 33 (3) 400-9 Link

Stehmeier P, Muller S Regulation of p53 family members by the ubiquitin-like SUMO system. DNA Repair (Amst) 2009. 8 (4) 491-8 Link

Klein UR, Haindl M, Nigg EA, Muller S RanBP2 and SENP3 function in a mitotic SUMO2/3 conjugation-deconjugation cycle on Borealin. Mol Biol Cell 2009. 20 (1) 410-8 Link

Muller S, Dobner T The adenovirus E1B-55K oncoprotein induces SUMO modification of p53. Cell Cycle 2008. 7 (6) 754-8 Link

Haindl M, Harasim T, Eick D, Muller S The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing. EMBO Rep 2008. 9 (3) 273-9 Link

Buschbeck M, Uribesalgo I, Ledl A, Gutierrez A, Minucci S, Muller S, Di Croce L PML4 induces differentiation by Myc destabilization. Oncogene 2007. 26 (23) 3415-22 Link

Mziaut H, Trajkovski M, Kersting S, Ehninger A, Altkrüger A, Lemaitre RP, Schmidt D, Saeger HD, Lee MS, Drechsel DN, Müller S, Solimena M Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5. Nat Cell Biol 2006. 8 (5) 435-45 Link

Bossis G, Malnou CE, Farras R, Andermarcher E, Hipskind R, Rodriguez M, Schmidt D, Muller S, Jariel-Encontre I, Piechaczyk M Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. Mol Cell Biol 2005. 25 (16) 6964-79 Link

Ledl A, Schmidt D, Müller S Viral oncoproteins E1A and E7 and cellular LxCxE proteins repress SUMO modification of the retinoblastoma tumor suppressor. Oncogene 2005. 24 (23) 3810-8 Link

Trajkovski M, Mziaut H, Altkrüger A, Ouwendijk J, Knoch KP, Müller S, Solimena M Nuclear translocation of an ICA512 cytosolic fragment couples granule exocytosis and insulin expression in {beta}-cells. J Cell Biol 2004. 167 (6) 1063-74 Link

Müller S, Ledl A, Schmidt D SUMO: a regulator of gene expression and genome integrity. Oncogene 2004. 23 (11) 1998-2008 Link

Schmidt D, Müller S PIAS/SUMO: new partners in transcriptional regulation. Cell Mol Life Sci 2003. 60 (12) 2561-74 Link

García-Estrada C, Reguera RM, Villa H, Requena JM, Müller S, Pérez-Pertejo Y, Balaña-Fouce R, Ordóñez D Identification of a gene in Leishmania infantum encoding a protein that contains a SP-RING/MIZ zinc finger domain. Biochim Biophys Acta 2003. 1629 (1-3) 44-52 Link

Netzer C, Bohlander SK, Rieger L, Müller S, Kohlhase J Interaction of the developmental regulator SALL1 with UBE2I and SUMO-1. Biochem Biophys Res Commun 2002. 296 (4) 870-6 Link

Kirsh O, Seeler JS, Pichler A, Gast A, Müller S, Miska E, Mathieu M, Harel-Bellan A, Kouzarides T, Melchior F, Dejean A The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J 2002. 21 (11) 2682-91 Link

Schmidt D, Müller S Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc Natl Acad Sci U S A 2002. 99 (5) 2872-7 Link

Müller S, Hoege C, Pyrowolakis G, Jentsch S SUMO, ubiquitin's mysterious cousin. Nat Rev Mol Cell Biol 2001. 2 (3) 202-10 Link

Lehembre F, Müller S, Pandolfi PP, Dejean A Regulation of Pax3 transcriptional activity by SUMO-1-modified PML. Oncogene 2001. 20 (1) 1-9 Link

Muller S, Berger M, Lehembre F, Seeler JS, Haupt Y, Dejean A c-Jun and p53 activity is modulated by SUMO-1 modification. J Biol Chem 2000. 275 (18) 13321-9 Link

Zhong S, Müller S, Ronchetti S, Freemont PS, Dejean A, Pandolfi PP Role of SUMO-1-modified PML in nuclear body formation. Blood 2000. 95 (9) 2748-52 Link

Lehembre F, Badenhorst P, Müller S, Travers A, Schweisguth F, Dejean A Covalent modification of the transcriptional repressor tramtrack by the ubiquitin-related protein Smt3 in Drosophila flies. Mol Cell Biol 2000. 20 (3) 1072-82 Link

Müller S, Dejean A Viral immediate-early proteins abrogate the modification by SUMO-1 of PML and Sp100 proteins, correlating with nuclear body disruption. J Virol 1999. 73 (6) 5137-43 Link

Müller S, Miller WH, Dejean A Trivalent antimonials induce degradation of the PML-RAR oncoprotein and reorganization of the promyelocytic leukemia nuclear bodies in acute promyelocytic leukemia NB4 cells. Blood 1998. 92 (11) 4308-16 Link

Müller S, Matunis MJ, Dejean A Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J 1998. 17 (1) 61-70 Link

Dümmler K, Müller S, Seitz HJ Regulation of adenine nucleotide translocase and glycerol 3-phosphate dehydrogenase expression by thyroid hormones in different rat tissues. Biochem J 1996. 317 ( Pt 3) 913-8 Link

Müller S, Seitz HJ Cloning of a cDNA for the FAD-linked glycerol-3-phosphate dehydrogenase from rat liver and its regulation by thyroid hormones. Proc Natl Acad Sci U S A 1994. 91 (22) 10581-5 Link

Watts RA, Winska-Wiloch H, Muller S, Isenberg DA Analysis of factors affecting human hybridoma production. Hum Antibodies Hybridomas 1990. 1 (3) 160-5 Link

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

Hannah Mende

Jan Keiten-Schmitz

Judith Dönig

Kristina Wagner

Linda Röder

Dr. Luca Mendler

Paul Hotz

Tabea Stark

Dr. Upayan Patra

Past Members:

Kathrin Schunck (Geb. Kunz)

Mechanistic and functional aspects of SUMO-SIM interactions

The SUMO system in mammalian ribosome biogenesis