TY  - JOUR
A1  - Klein-Hessling, Stefan
A1  - Muhammad, Khalid
A1  - Klein, Matthias
A1  - Pusch, Tobias
A1  - Rudolf, Ronald
A1  - Flöter, Jessica
A1  - Qureischi, Musga
A1  - Beilhack, Andreas
A1  - Vaeth, Martin
A1  - Kummerow, Carsten
A1  - Backes, Christian
A1  - Schoppmeyer, Rouven
A1  - Hahn, Ulrike
A1  - Hoth, Markus
A1  - Bopp, Tobias
A1  - Berberich-Siebelt, Friederike
A1  - Patra, Amiya
A1  - Avots, Andris
A1  - Müller, Nora
A1  - Schulze, Almut
A1  - Serfling, Edgar
T1  - NFATc1 controls the cytotoxicity of CD8\(^{+}\) T cells
JF  - Nature Communications
N2  - Cytotoxic T lymphocytes are effector CD8\(^{+}\) T cells that eradicate infected and malignant cells. Here we show that the transcription factor NFATc1 controls the cytotoxicity of mouse cytotoxic T lymphocytes. Activation of Nfatc1\(^{-/-}\) cytotoxic T lymphocytes showed a defective cytoskeleton organization and recruitment of cytosolic organelles to immunological synapses. These cells have reduced cytotoxicity against tumor cells, and mice with NFATc1-deficient T cells are defective in controlling Listeria infection. Transcriptome analysis shows diminished RNA levels of numerous genes in Nfatc1\(^{-/-}\) CD8\(^{+}\) T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1\(^{-/-}\), but not Nfatc2\(^{-/-}\) CD8\(^{+}\) T cells have an impaired metabolic switch to glycolysis, which can be restored by IL-2. Genome-wide ChIP-seq shows that NFATc1 binds many genes that control cytotoxic T lymphocyte activity. Together these data indicate that NFATc1 is an important regulator of cytotoxic T lymphocyte effector functions.
KW  - cytotoxic T cells
KW  - lymphocyte activation
KW  - signal transduction
KW  - gene regulation
KW  - immune cells
KW  - NFATc1
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170353
VL  - 8
IS  - 511
ER  - 
TY  - JOUR
A1  - Sanges, C.
A1  - Scheuermann, C.
A1  - Zahedi, R. P.
A1  - Sickmann, A.
A1  - Lamberti, A.
A1  - Migliaccio, N.
A1  - Baljuls, A.
A1  - Marra, M.
A1  - Zappavigna, S.
A1  - Rapp, U.
A1  - Abbruzzese, A.
A1  - Caraglia, M.
A1  - Arcari, P.
T1  - Raf kinases mediate the phosphorylation of eukaryotic translation elongation factor 1A and regulate its stability in eukaryotic cells
JF  - Cell Death & Disease
N2  - We identified eukaryotic translation elongation factor 1A (eEF1A) Raf-mediated phosphorylation sites and defined their role in the regulation of eEF1A half-life and of apoptosis of human cancer cells. Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B-and C-Raf. Interestingly, S21 belongs to the first eEF1A GTP/GDP-binding consensus sequence. Phosphorylation of S21 was strongly enhanced when both eEF1A isoforms were preincubated prior the assay with C-Raf, suggesting that the eEF1A isoforms can heterodimerize thus increasing the accessibility of S21 to the phosphate. Overexpression of eEF1A1 in COS 7 cells confirmed the phosphorylation of T88 also in vivo. Compared with wt, in COS 7 cells overexpressed phosphodeficient (A) and phospho-mimicking (D) mutants of eEF1A1 (S21A/D and T88A/D) and of eEF1A2 (S21A/D), resulted less stable and more rapidly proteasome degraded. Transfection of S21 A/D eEF1A mutants in H1355 cells increased apoptosis in comparison with the wt isoforms. It indicates that the blockage of S21 interferes with or even supports C-Raf induced apoptosis rather than cell survival. Raf-mediated regulation of this site could be a crucial mechanism involved in the functional switching of eEF1A between its role in protein biosynthesis and its participation in other cellular processes.
KW  - signal transduction
KW  - mass spectrometry
KW  - elongation
KW  - protein docking
KW  - factor EEF1A2
KW  - cancer-cells
KW  - lung cancer
KW  - EF-1A
KW  - Raf kinases
KW  - aminoacyl-transfer-RNA
KW  - tyrosine phosphorylation
KW  - factor 1-alpha
KW  - nucleotide exchange
KW  - polyarcylamide gels
KW  - chain
KW  - apoptosis
KW  - ubiquitin
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134673
VL  - 3
IS  - e276
ER  - 
TY  - JOUR
A1  - Müller, T.
A1  - Dieckmann, T.
A1  - Sebald, Walter
A1  - Oschkinat, H.
T1  - Aspects of receptor binding and signalling of interleukin-4 investigated by site-directed mutagenesis and NMR spectroscopy
N2  - Cytokines are hormones that carry information from ceJI to ceH. This information is read from their surface upon binding to transmembrane receptors and by the subsequent initiation of receptor oligomerization. An inftuence on this process through mutagenesis on the hormone surface is highly desirab)e for medical reasons. However, an understanding of hormone-receptor interactions requires insight into the structural changes introduced by the mutations. In this line structural studies on human TL-4 and the medically important IL-4 antagonists YI24D and Y124G are presented. The site a.round YI24 is an important epitope responsible for the a.bility of 11-4 t.o ca.use a signal in the target cells. It is shown that the local main-chain structure around residue 124 in the variants remains unchanged. A strategy is presented here which allows the study of these types of proteins and their variants by NMR which does not require carbon Iabeiied sa.mples.
KW  - Biochemie
KW  - Interleukin-4
KW  - protein structure
KW  - NMR
KW  - signal transduction
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62444
ER  -