Prof. Dr. Bettina Warscheid

Abteilung für Biochemie und Funktionelle Proteomik
Institut für Biologie II und BIOSS Centre for Biological Signalling Studies
Albert-Ludwigs-Universität Freiburg
Schänzlestraße 1
79104 Freiburg

Prof. Dr. Michael Reth

Molekulare Immunologie
Fakultät für Biologie
Albert-Ludwigs-Universität Freiburg
Schänzlestraße 18    
79104 Freiburg    

Tel. +49 (0) 761 203 2718    
michael.reth@bioss.uni-freiburg.de    

Project summary:

The role of phosphatases in B cell autoimmunity

B cell activation is mediated by multiple tyrosine phosphorylation events that are tightly controlled by protein tyrosine phosphatases (PTPs). The majority of these enzymes have a negative regulatory role and thus their dysfunction can lead to hyperactivity and auto-reactivity of B cells. We generated mice with a B-cell-specific deficiency for the protein tyrosine phosphatase 1B (PTP1B, encoded by the Ptpn1 gene). We observed that aged animals develop systemic autoimmunity. Our ex vivo studies showed that the PTP1B inhibits TNFR family receptors (CD40, BAFFR) and TLR4 signalling in B cells. We also observed reduced Ptpn1 mRNA levels in human rheumatoid arthritis patients. Other PTPs such as SHP-1 and CD148 are also connected to autoimmunity. These PTPs can have different subcellular locations. For example, SHP-1 is a cytoplasmic enzyme, CD148 is a receptor PTP at the plasma membrane, while PTP1B is localized to the cytoplasmic surface of the endoplasmic reticulum (ER). Using large-scale quantitative phosphoproteomics assays, we will comprehensively identify the substrates of these three different PTPs in B cells. Moreover, purifying cellular fractions (ER, plasma membrane) and analysing the compartment-specific substrates of the PTPs will allow us to determine key signalling events at these intracellular locations. We will then functionally validate the found substrates in mouse and in human samples. These results will help to clarify the key distinctions and redundancies in the tyrosine phosphatase network in B cells and may lead to a better understanding of the molecular mechanisms of B cell autoimmunity.

Fig. 1. Establishment of the protein tyrosine phosphatase (PTP)-substrate network in B cells.
Publications P 05:

Jumaa, H., Caganova, M., McAllister, EJ., Hoenig, L., He, X., Saltukoglu, D., Brenker, K., Köhler, M., Leben, R., Hauser, AE., Niesner, R., Rajewsky, K., Reth, M., and Jellusova, J. (2020) Immunoglobulin expression in the endoplasmic reticulum shapes the metabolic fitness of B lymphocytes. Life Sci. Alliance 6, e202000700.

Meyer, S.J., Böser, A., Korn, M., Koller, C., Bertocci, B., Reimann, R., Warscheid, B., and Nitschke, L. (2020) Cullin 3 Is crucial for pro-B cell proliferation, interacts with CD22, and controls CD22 internalization on B cells. J. Immunol. 204, 3360-3374.

Reimann, L.* Schwäble, A.N.*, Fricke, A., Muehlhaeuser, W.W.D., Leber, Y., Lohanadan, K., Puchinger, M., Schäuble, S., Fässler, E., Wiese, H., Reichenbach, C., Knapp, B., Peikert, C.D., Drepper, F., Hahn, U., Kreutz, C., van der Ven, P.F.M., Radziwill, G., Djinović-Carugo, K., Fürst, D.O., and Warscheid, B. (2020) Phosphoproteomics identifies dual-site phosphorylation in an extended basophilic motif regulating FILIP1-mediated degradation of filamin-C, Commun. Biol. 3, 253. *shared first authorships

Gottwick, C., He, X., Hofmann, A., Vesper, N., Reth, M., and Yang J. (2019) A symmetric geometry of trans-membrane domains inside the B cell antigen receptor complex. Proc. Natl. Acad. Sci. USA 116, 13468-13473.

Hörner, M.*, Eble, J.*, Yousefi, S.O.*, Schwarz, J.*, Warscheid, B., Weber, W., and Schamel, W.W. (2019) Light-controlled affinity purification of protein complexes exemplified by the resting ZAP70 interactome, Front. Immunol. 10, 226. *shared first authorships

He, X., Klasener, K., Iype, J.M., Becker, M., Maity, P.C., Cavallari, M., Nielsen, P.J., Yang, J., and Reth, M. (2018). Continuous signaling of CD79b and CD19 is required for the fitness of Burkitt lymphoma B cells. EMBO J. 37, e97980.

Dolezal, E., Infantino, S., Drepper, F., Börsig, T., Wossning, T., Warscheid, B., Tarlinton, D., Jumaa, H., Medgyesi, D., and Reth, M. (2017). The BTG2/PRMT1 module limits pre-B cell expansion by regulating the CDK4/Cyclin D3 complex, Nat. Immunol. 18, 911-920.

Mokada-Gopal, L., Boeser, A., Drepper, F., Lehmann, C., Dudziak, D., Warscheid, B., and Voehringer, D. (2017). Identification of novel STAT6-regulated proteins in mouse B cells by comparative transcriptome and proteome analysis, J. Immunol. 198, 3737-3745.

Ruf, S., Heberle, A.M., Langelaar-Makkinje, M., Gelino, S., Wilkinson, D., Gerbeth, G., Schwarz, J.J., Holzwarth, B., Warscheid, B., Meisinger, C., van Vugt, M.A., Baumeister, R., Hansen, M, Thedieck, K. (2017). PLK1 (polo like kinase 1) inhibits MTOR complex 1 and promotes autophagy. Autophagy, 13, 486-505.

Becker, M., Hobeika, E., Jumaa, H., Reth, M., and Maity, PC. (2017). CXCR4 signaling and function require the expression of the IgD-class B-cell antigen receptor. Proc. Natl. Acad. Sci. USA 114, 5231-5236.

Hobeika, E., Nielsen, P.J., and D. Medgyesi. (2015). Signaling mechanisms regulating B-lymphocyte activation and tolerance. J Mol Med 93, 143-158.

Wiese, H., Gelis, L., Wiese, S., Reichenbach, C., Jovancevic, N., Osterloh, M., Meyer, H.E., Neuhaus, E.M., Hatt, H.H., Radziwill, G., and Warscheid, B. (2015). Quantitative phosphoproteomics reveals the protein tyrosine kinase Pyk2 as a central effector of olfactory receptor signaling in prostate cancer cells. Biochim Biophys Acta 1854, 632-640.