Characterisation of the functions of SLy1 and SLy2 in the immune system
Final Report Abstract
SLy1 was found to be exclusively expressed in lymphoid organs and was identified as an X- chromosomally encoded SH3 protein that is specifically phosphorylated at Ser27 upon B and T cell receptor engagement. Moreover, inhibitor studies implied that this antigen receptor-mediated phosphorylation is PI3-Kinase- and PKC- dependent. These studies therefore defined SLy1 as a previously unrecognized target for antigen receptor signal transduction and suggested that it may play a role in adaptive immunity. A mouse line harbouring a mutant version of SLy1 which lacks essential parts of the NLS domain as well as the Ser27 residue was established in our laboratory. The mice show severe defects in T and B cell functions. To rule out any dominant-negative effect of this remaining mutant-protein, a complete SLy1-KO mouse line was generated. These mice show similar defects in T and B cell development and function. Detailed analysis of T cell development in the thymus revealed an anti-apoptotic role for SLy1 in developing thymocytes. The role of SLy1 in the periphery and during induced immune responses is still under investigation. In cooperation with Sasha Krupnick (St. Louis, USA) we now started to unravel the role of SLy1 in NK cells in lung carcinoma. SLy2 (SAMSN1 or Nash1/HACS1) was first identified in a cDNA library screen of genes differentially expressed in multiple myeloma. This deregulated expression in different malignancies was matched by findings that the genomic region of SLy2 (21q11.2) is frequently targeted by translocation events in hematopoietic malignancies. Western blot analyses showed strong expression of SLy2 in lymphoid organs, yet, lower expression levels were also identified in brain, lung, pancreas and ovary. According to Zhu and colleagues, SLy2 expression is up-regulated in human B cells upon stimulation with interleukin (IL)-4, IL-13, IL-4+CD40L, and IL-4+anti-IgM. In murine spleen B cells, SLy2 was also up-regulated by LPS, whereas IL-13 had no effects. The induction of SLy2 by IL-4 was reported to be Stat6-dependent and was impaired by inhibitors of PI3K, PKC, and NFκB. Moreover, overexpression of the protein in B cells lead to a plasma cell-like phenotype (CD138high, increased secretion of IgM) and an attenuated rate of proliferation. In our ongoing work we examined the immunological role of SLy2 with the help of SLy2-KO and TG animals. The investigations unravelled a novel intracellular mechanism by which abundance of B-1 lymphocytes and their capacity to produce pneumococcal polysaccharidespecific antibodies were inhibited following SLy2 overexpression, suggesting that SLy2 amplification, as it was found in human Down Syndrome patients, might contribute to a general susceptibility to Streptococcus pneumonia infections. This hypothesis is further supported by preliminary data from BALB/c and SLy2-KO mice. In conclusion, these data strongly propose SLy2 as an immuno-inhibitory adaptor protein, which might represent a potential future therapeutic target for prevention of pneumococcal infections.
Publications
- (2009) The orphan adapter protein SLY1 as a novel anti-apoptotic protein required for thymocyte development. BMC Immunol 10: 38
Reis, B., Pfeffer, K., Beer-Hammer, S.
(See online at https://doi.org/10.1186/1471-2172-10-38) - (2010) The nucleo-cytoplasmic protein SLy2 targets the SAP30/HDAC1 complex. Int J Biochem Cell Biol 42: 1472-1481
Brandt, S., Beuter-Gunia, C., Schuster, M., Hausser, A., Schmitz, I., Beer-Hammer, S.
- (2011) The immunoinhibitory adapter protein SRC homology domain 3 lymphocyte protein 2 (SLy2) regulates actin dynamics and B cell spreading. J Biol Chem 286: 13489-13501
von Holleben, M., Gohla, A., Janssen, K.-P., Iritani, B., Beer-Hammer, S.
- (2013) Modified mRNA encoding Foxp3 protects against allergic asthma in mice through an IL-23/IL-17A-dependent mechanism. J Clin Invest, 123(3): 1216-1228
Mays, L.E., Ammon-Treiber, S., Mothes, B., Müller-Hermelink, E.S., Grimm, M., Mezger M., Beer-Hammer, S., Nürnberg, B., Schwab, M., Handgretinger, R., Idzko, M., Hartl, D., Kormann, M.S.D.
- (2013) Primary cilia migration depends on G-protein signaling in mammalian epithelium. Nat Cell Biol, 15(9):1107-15
Ezan, J., Lasvaux, L., Gezer, A., Novakovic, A., May-Simera, H., Belotti, E., Lhoumeau, A.-C., Birnbaumer, L., Beer-Hammer, S., Borg, J.-P., Le Bivic, A., Nürnberg, B., Sans, N., Montcouquiol, M.
- (2013) Toxoplasma gondii replication is controlled by the murine guanylate binding protein 2 (mGBP2). Proc Natl Aacad Sci USA, 110(1): 294-299
Degrandi, D., Kravets E., Konermann, C., Beuter-Gunia, C., Beer-Hammer, S., Pfeffer, K.
- SLy2 controls the antibody response to pneumococcal vaccine through an IL-5Ra-dependent mechanism in B-1 cells. Eur J Immunol, Vol 45 Issue 1, January 2015, Pages 60-70. First published: 21 October 2014
Schmitt, F., Schäll, D., Bucher, K., Theresa Isabell Schindler, Hector, A., Tilo Biedermann, Michael Zemlin, Hartl, D., Beer-Hammer, S.
(See online at https://doi.org/10.1002/eji.201444882)
