TY  - JOUR
A1  - Karunakaran, Mohindar M.
A1  - Subramanian, Hariharan
A1  - Jin, Yiming
A1  - Mohammed, Fiyaz
A1  - Kimmel, Brigitte
A1  - Juraske, Claudia
A1  - Starick, Lisa
A1  - Nöhren, Anna
A1  - Länder, Nora
A1  - Willcox, Carrie R.
A1  - Singh, Rohit
A1  - Schamel, Wolfgang W.
A1  - Nikolaev, Viacheslav O.
A1  - Kunzmann, Volker
A1  - Wiemer, Andrew J.
A1  - Willcox, Benjamin E.
A1  - Herrmann, Thomas
T1  - A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing
JF  - Nature Communications
N2  - Butyrophilin (BTN)–3A and BTN2A1 molecules control the activation of human Vγ9Vδ2 T cells during T cell receptor (TCR)-mediated sensing of phosphoantigens (PAg) derived from microbes and tumors. However, the molecular rules governing PAg sensing remain largely unknown. Here, we establish three mechanistic principles of PAg-mediated γδ T cell activation. First, in humans, following PAg binding to the intracellular BTN3A1-B30.2 domain, Vγ9Vδ2 TCR triggering involves the extracellular V-domain of BTN3A2/BTN3A3. Moreover, the localization of both protein domains on different chains of the BTN3A homo-or heteromers is essential for efficient PAg-mediated activation. Second, the formation of BTN3A homo-or heteromers, which differ in intracellular trafficking and conformation, is controlled by molecular interactions between the juxtamembrane regions of the BTN3A chains. Finally, the ability of PAg not simply to bind BTN3A-B30.2, but to promote its subsequent interaction with the BTN2A1-B30.2 domain, is essential for T-cell activation. Defining these determinants of cooperation and the division of labor in BTN proteins improves our understanding of PAg sensing and elucidates a mode of action that may apply to other BTN family members.
KW  - gammadelta T cells
KW  - immunosurveillance
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358179
VL  - 14
ER  - 
TY  - JOUR
A1  - Chithelen, Janice
A1  - Franke, Hannah
A1  - Länder, Nora
A1  - Grafen, Anika
A1  - Schneider-Schaulies, Jürgen
T1  - The sphingolipid inhibitors ceranib-2 and SKI-II reduce measles virus replication in primary human lymphocytes: effects on mTORC1 downstream signaling
JF  - Frontiers in Physiology
N2  - The bioactive sphingolipids ceramide and sphingosine-1-phosphate (S1P) are involved in the regulation of cell homeostasis and activity ranging from apoptosis to proliferation. We recently described that the two compounds ceranib-2 (inhibiting acid ceramidase) and SKI-II [inhibiting the sphingosine kinases 1 and − 2 (SphK1/2)] reduce mTORC1 activity and measles virus (MV) replication in human primary peripheral blood lymphocytes (PBL) by about one log step. We now further investigated whether mTORC1 downstream signaling and viral protein expression may be affected by ceranib-2 and/or SKI-II. Western blot analyses showed that in uninfected cells the phosphorylation of the eukaryotic initiation factor 4E (eIF4E) was reduced by both inhibitors. Interestingly, MV infection led to an increase of rpS6 protein levels and phosphorylation of eIF4E. Treatment with both inhibitors reduced the rpS6 protein expression, and in addition, SKI-II reduced rpS6 phosphorylation. The phosphorylation of eIF4E was slightly reduced by both inhibitors. In addition, SKI-II led to reduced levels of IKK in MV-infected cells. Both inhibitors reduced the expression of viral proteins and the titers of newly synthesized MV by approximately one log step. As expected, SKI-II and rapamycin reduced also the virally encoded GFP expression; however, ceranib-2 astonishingly led to increased levels of GFP fluorescence. Our findings suggest that the inhibitors ceranib-2 and SKI-II act via differential mechanisms on MV replication. The observed effects on mTORC1 downstream signaling, predominantly the reduction of rpS6 levels by both inhibitors, may affect the translational capacity of the cells and contribute to the antiviral effect in human primary PBL.
KW  - acid ceramidase inhibitor ceranib-2
KW  - sphingosine kinase inhibitor SKI-II
KW  - mTORC1
KW  - translation
KW  - measles virus
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265988
SN  - 1664-042X
VL  - 13
ER  -