TY  - JOUR
A1  - Engel, Katharina
A1  - Rudelius, Martina
A1  - Slawska, Jolanta
A1  - Jacobs, Laura
A1  - Abhari, Behnaz Ahangarian
A1  - Altmann, Bettina
A1  - Kurutz, Julia
A1  - Rathakrishnan, Abirami
A1  - Fernández-Sáiz, Vanesa
A1  - Brunner, Andrä
A1  - Targosz, Bianca-Sabrina
A1  - Loewecke, Felicia
A1  - Gloeckner, Christian Johannes
A1  - Ueffing, Marius
A1  - Fulda, Simone
A1  - Pfreundschuh, Michael
A1  - Trümper, Lorenz
A1  - Klapper, Wolfram
A1  - Keller, Ulrich
A1  - Jost, Philipp J.
A1  - Rosenwald, Andreas
A1  - Peschel, Christian
A1  - Bassermann, Florian
T1  - USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B-cell lymphoma
JF  - EMBO Molecular Medicine
N2  - The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC‐induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X‐linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B‐cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. We show that high USP9X/XIAP expression is associated with shorter event‐free survival in patients treated with spindle poison‐containing chemotherapy. Accordingly, aggressive B‐cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine Eμ‐Myc lymphoma model. Together, we specify the USP9X–XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B‐cell lymphoma.
KW  - B‐cell lymphoma
KW  - mitosis
KW  - ubiquitin
KW  - USP9X
KW  - XIAP
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165016
VL  - 8
ER  - 
TY  - JOUR
A1  - Weinelt, Nadine
A1  - Karathanasis, Christos
A1  - Smith, Sonja
A1  - Medler, Juliane
A1  - Malkusch, Sebastian
A1  - Fulda, Simone
A1  - Wajant, Harald
A1  - Heilemann, Mike
A1  - van Wijk, Sjoerd J. L.
T1  - Quantitative single‐molecule imaging of TNFR1 reveals zafirlukast as antagonist of TNFR1 clustering and TNFα‐induced NF‐ĸB signaling
JF  - Journal of Leukocyte Biology
N2  - TNFR1 is a crucial regulator of NF‐ĸB‐mediated proinflammatory cell survival responses and programmed cell death (PCD). Deregulation of TNFα‐ and TNFR1‐controlled NF‐ĸB signaling underlies major diseases, like cancer, inflammation, and autoimmune diseases. Therefore, although being routinely used, antagonists of TNFα might also affect TNFR2‐mediated processes, so that alternative approaches to directly antagonize TNFR1 are beneficial. Here, we apply quantitative single‐molecule localization microscopy (SMLM) of TNFR1 in physiologic cellular settings to validate and characterize TNFR1 inhibitory substances, exemplified by the recently described TNFR1 antagonist zafirlukast. Treatment of TNFR1‐mEos2 reconstituted TNFR1/2 knockout mouse embryonic fibroblasts (MEFs) with zafirlukast inhibited both ligand‐independent preligand assembly domain (PLAD)‐mediated TNFR1 dimerization as well as TNFα‐induced TNFR1 oligomerization. In addition, zafirlukast‐mediated inhibition of TNFR1 clustering was accompanied by deregulation of acute and prolonged NF‐ĸB signaling in reconstituted TNFR1‐mEos2 MEFs and human cervical carcinoma cells. These findings reveal the necessity of PLAD‐mediated, ligand‐independent TNFR1 dimerization for NF‐ĸB activation, highlight the PLAD as central regulator of TNFα‐induced TNFR1 oligomerization, and demonstrate that TNFR1‐mEos2 MEFs can be used to investigate TNFR1‐antagonizing compounds employing single‐molecule quantification and functional NF‐ĸB assays at physiologic conditions.
KW  - Single‐Molecule Localization Microscopy (SMLM)
KW  - Pre‐Ligand Assembly Domain (PLAD)
KW  - Cysteine‐Rich Domain (CRD)
KW  - CysLTR1
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215960
VL  - 109
IS  - 2
SP  - 363
EP  - 371
ER  -