{"id":5421,"date":"2019-09-11T16:20:29","date_gmt":"2019-09-11T14:20:29","guid":{"rendered":"https:\/\/www.resist-cluster.de\/?page_id=5421"},"modified":"2025-07-17T13:47:25","modified_gmt":"2025-07-17T11:47:25","slug":"project-b12","status":"publish","type":"page","link":"https:\/\/www.resist-cluster.de\/en\/research\/project-area-b\/project-b12\/","title":{"rendered":"Project B12"},"content":{"rendered":"

<\/div>
<\/div>
<\/div>

So-called ubiquitins can play an important role during bacterial infections. Are they suitable for new therapeutic approach?<\/h1><\/div>

Prof. Schl\u00fcter<\/a><\/p><\/h2><\/div>

<\/div><\/div><\/div><\/div><\/div>
<\/path><\/svg><\/div>
<\/div><\/div><\/div>
<\/div><\/div><\/div><\/div><\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div><\/div><\/div>

What is this research project about?<\/h1><\/div>
<\/a><\/span><\/div>

Diagram of implant-associated infections<\/p>\n<\/div>

<\/div><\/div><\/div>

What is this research project about?<\/h1><\/div>

The risk and the course of serious bacterial infections are primarily determined by the interaction between the specific bacterium and the infected human. The susceptibility to infection is critically determined by individual host-specific factors including an underlying immunodeficiency, the age and the existence of implants. Bacterial pathogens exploit the impaired resistance of humans to cause infections. At the same time, practically all relevant bacterial pathogens actively weaken the immune system of the infected individuals and thereby exacerbate the infection. Due to the increasing antibiotic resistance of bacteria, antibiotic therapy becomes more challenging. In this regard, the prevention of an impairment of the immune system and its strengthening constitute an innovative therapeutic option.<\/p>\n<\/div>

<\/div><\/div><\/div><\/div><\/div>
<\/path><\/svg><\/div>
<\/div><\/div><\/div>
<\/div><\/div><\/div><\/div><\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div>

What’s the current status?<\/h1><\/div>
<\/div><\/div><\/div>

In order to rapidly sense pathogens, the immune system possesses several receptors which identify invading bacteria. Upon engagement of these receptors, defense mechanisms are activated swiftly in immune cells which trigger antibacterial immune reactions within minutes. These immune reactions are decisively dependent on the posttranslational modification of host cell proteins. This includes the ubiquitination of host cell proteins by either the accumulation of ubiquitin molecules on the protein or the cleavage of ubiquitin molecules. In both acute and chronic infections, the ubiquitination status of immunologically important signaling molecules in infected cells and leukocytes is of fundamental importance for the course of infection. For this reason, numerous bacteria have developed mechanisms to manipulate the ubiquitination of host proteins. A therapeutic manipulation of the ubiquitination processes potentially offers new treatment options of infectious diseases beyond antibiotics.<\/p>\n<\/div>

<\/div><\/div><\/div>
<\/span><\/div><\/div>

The immune system has to defend itself against pathogens. The photo shows an electron micrograph of the bacterium Acinetobacter baumannii<\/em>.\u00a0Source: Gudrun Holland; colouring: Michael Laue\/RKI<\/p>\n<\/div>

<\/div><\/div><\/div>
<\/div>
<\/div>
<\/div>
<\/div><\/div><\/div><\/div><\/div>
<\/div>
<\/div>
<\/div>
<\/div><\/div><\/div><\/div><\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div><\/div><\/div>

What are the project goals?<\/h1><\/div>

A prerequisite for the development of novel therapeutics influencing the ubiquitination status of host signaling molecules is a profound understanding of the immunological function of ubiquitin attaching and cleaving proteases in bacterial infections. A combined effort on experimental and clinical studies will allow the identification of particularly important ubiquitin regulating host cell proteins. These studies will also provide the basis for the targeted development of therapeutics strengthening the antibacterial immune response by ubiquitin modifications.<\/p>\n<\/div><\/div><\/div>

<\/div><\/div><\/div>
<\/div>
<\/div>
<\/div>
<\/div><\/div><\/div><\/div><\/div>
<\/div>
<\/div>
<\/div>
<\/div><\/div><\/div><\/div><\/div>
<\/div>
<\/div>
<\/div>

How do we get there?<\/h1><\/div>
<\/div><\/div><\/div>

In order to evaluate the potential of ubiquitin modulating substances as antiinfectives and autoinflammatory diseases driven by bacteria, we will continue our work on the functional significance and individual domains of deubiquitinating enzymes (DUBs). We have already performed corresponding investigations on the DUBs TNFAIP3, CYLD and OTUB1 and we identified specific domains of these DUBs, which mediate the successful control of bacterial infections (Just et al., 2016; Wex et al., 2016; Wang et al., 2013; Wang et al., 2019; Nishanth et al., 2013). To further study structure\/function relation of DUBs, we currently generate new innovative mouse models.
\nWe will use established experimental models such as Listeria monocytogenes and Staphylococcus aureus infections. We combine these infection models with studies on the function of DUBs and S. aureus in atopic dermatitis, since in AD, S. aureus increasingly causes infection and aggravates atopic dermatitis (cooperation T. Werfel, L. R\u00f6ssner; project A3<\/a>, A4<\/a>, B5<\/a>, RESIST cohort<\/a>). These studies show that individual DUBs are increasingly expressed in AD and weaken the control of S. aureus by macrophages.
\nOn the basis of these data, we will develop DUB inhibitors directed against the identified immunologically important domains of DUBs and evaluate these inhibitors in the aforementioned model infections.<\/p>\n<\/div>

<\/div><\/div><\/div>
<\/div>
<\/span><\/div><\/div>

Electron microscope image of Listeria monocytogenes<\/em>. Scale = 1 \u00b5m \u00a9 Petra Kaiser\/RKI<\/p>\n<\/div>

<\/div>
<\/div><\/div><\/div><\/div><\/div>
<\/div>
<\/div>
<\/div>
<\/div><\/div><\/div><\/div><\/div>
<\/path><\/svg><\/div>
<\/div><\/div><\/div>
<\/div><\/div><\/div><\/div><\/div><\/div>
<\/div>
<\/div>
<\/div>

Projectleaders<\/h1><\/div>

Project title: Structural and functional analysis of deubiquitinating enzymes as regulators and therapeutic targets in bacterial infections<\/h4><\/div>
<\/div><\/div><\/div><\/div><\/div>
<\/a><\/span><\/div>
<\/div>
<\/div>
<\/div>

Prof. Dr. Dirk Schl\u00fcter<\/h3><\/div>

Project: B12<\/a><\/h3><\/div>
<\/div>
<\/div>
<\/div>
CV & VIDEO<\/span><\/a><\/div>
<\/div><\/div><\/div>\n
<\/span><\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div><\/div><\/div>\n
<\/span><\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div><\/div><\/div>\n
<\/span><\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div><\/div><\/div>\n<\/div><\/div>
<\/path><\/svg><\/div>
<\/div><\/div><\/div>
<\/div><\/div><\/div><\/div><\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div>
<\/div><\/div><\/div>

Project B12 Publications<\/h1><\/div>

Publications 2025<\/strong><\/p>\n

Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters Staphylococcus aureus control<\/strong><\/a> C. Schmidt, K. Harit, S. Traidl, M. Naumann, T. Werfel, L. M. Roesner, et al. Front Immunol<\/strong> 2025 Vol. 16 Pages 1507989 Accession Number: 39958342 PMCID: PMC11827430 DOI: 10.3389\/fimmu.2025.1507989<\/p>\n

Transmissible Staphylococcus pseudintermedius thwarts neutrophil extracellular trap-driven containment to promote invasive disease<\/strong><\/a> R. Haller, Y. Cai, N. de Buhr, J. C. Rieder, D. Schl\u00fcter, C. Baier, et al. Emerg Microbes Infect<\/strong> 2025 Vol. 14 Issue 1 Pages 2482709 Accession Number: 40172876 PMCID: PMC12001851 DOI: 10.1080\/22221751.2025.2482709<\/p>\n

Publications 2024<\/strong><\/p>\n

Cross-regulation of Listeria monocytogenes and the host ubiquitin system in listeriosis<\/b><\/a>. Zhuang, Y., J. B. Fischer, G. Nishanth, and D. Schl\u00fcter. 2024.\u00a0 Eur J Cell Biol<\/strong> 103: 151401.<\/p>\n

Publications 2023<\/strong><\/p>\n

OTUB1 inhibits breast cancer by non-canonically stabilizing CCN6.<\/strong><\/a>\u00a0Zhao Y, Ruan J, Li Z, Su X, Chen K, Lin Y, Cai Y, Wang P, Liu B, Schl\u00fcter D, Liang G, Wang X. Clin Transl Med<\/strong>. 2023 Aug;13(8):e1385.<\/p>\n

Publications 2022<\/strong><\/p>\n

Deubiquitinating enzymes (DUBs): decipher underlying basis of neurodegenerative diseases.\u00a0<\/strong><\/a>Liu B, Ruan J, Chen M, Li Z, Manjengwa G, Schl\u00fcter D, Song W, Wang X.\u00a0 Mol<\/strong> Psychiatry<\/strong>. 2022 Jan;27(1):259-268.<\/p>\n

Publications 2021<\/strong><\/p>\n

Extracellular vesicles in neuroinflammation: Pathogenesis, diagnosis, and therapy<\/strong><\/a> J. Ruan, X. Miao, D. Schl\u00fcter, L. Lin and X. Wang Molecular Therapy: The Journal of the American Society of Gene Therapy <\/strong>2021 Vol<\/strong>. 29 Issue 6 Pages 1946-1957 DOI: 10.1016\/j.ymthe.2021.04.020<\/p>\n

Ovarian tumor domain proteases in pathogen infection<\/strong><\/a>. Review. Trends in Microbiology<\/strong>. Dirk Schl\u00fcter, EricSchulze-Niemand, Matthias Stein, Michael Naumann, online 17 May 2021 https:\/\/doi.org\/10.1016\/j.tim.2021.04.002<\/p>\n

OTUB1 prevents lethal hepatocyte necroptosis through stabilization of c-IAP1 during murine liver inflammation.<\/strong> <\/a>Koschel J, Nishanth G, Just S, Harit K, Kr\u00f6ger A, Deckert M, Naumann M, Schl\u00fcter D. Cell Death Differ<\/strong>. 2021 Mar 12. doi: 10.1038\/s41418-021-00752-9. Online ahead of print. PMID: 33712742<\/p>\n

Publications 2020<\/strong><\/p>\n

Deubiquitinating enzymes (DUBs): DoUBle-edged swords in CNS autoimmunity<\/strong><\/a>. J Neuroinflammation<\/strong>. Ruan J, Schl\u00fcter D, Wang X. 2020 Apr 6;17(1):102. doi: 10.1186\/s12974-020-01783-8. PMID: 32248814; PMCID: PMC7132956.<\/p>\n

Publications 2019<\/strong><\/p>\n

Diversity of Bacteria Exhibiting Bile Acid-inducible 7alpha-dehydroxylation Genes in the Human Gut<\/a><\/strong>. Vital M, Rud T, Rath S, Pieper DH, Schl\u00fcter D. Comput Struct Biotechnol J<\/strong> 2019;17:1016-1019<\/p>\n<\/div>

<\/div><\/div><\/div>

Publications of the Project B12<\/h1><\/div>
<\/span><\/div><\/div>
<\/div><\/div><\/div><\/div><\/div><\/div>
<\/div><\/div><\/div>
<\/div>
<\/div>
<\/div>
<\/div><\/div><\/div><\/div><\/div><\/p>\n","protected":false},"excerpt":{"rendered":"","protected":false},"author":1,"featured_media":0,"parent":5524,"menu_order":125,"comment_status":"closed","ping_status":"closed","template":"100-width.php","meta":{"footnotes":""},"class_list":["post-5421","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/www.resist-cluster.de\/en\/wp-json\/wp\/v2\/pages\/5421","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.resist-cluster.de\/en\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www.resist-cluster.de\/en\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www.resist-cluster.de\/en\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.resist-cluster.de\/en\/wp-json\/wp\/v2\/comments?post=5421"}],"version-history":[{"count":32,"href":"https:\/\/www.resist-cluster.de\/en\/wp-json\/wp\/v2\/pages\/5421\/revisions"}],"predecessor-version":[{"id":39289,"href":"https:\/\/www.resist-cluster.de\/en\/wp-json\/wp\/v2\/pages\/5421\/revisions\/39289"}],"up":[{"embeddable":true,"href":"https:\/\/www.resist-cluster.de\/en\/wp-json\/wp\/v2\/pages\/5524"}],"wp:attachment":[{"href":"https:\/\/www.resist-cluster.de\/en\/wp-json\/wp\/v2\/media?parent=5421"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}