TY  - JOUR
A1  - Rodrigues, Lénia
A1  - Popov, Nikita
A1  - Kaye, Kenneth M.
A1  - Simas, J. Pedro
T1  - Stabilization of Myc through Heterotypic Poly-Ubiquitination by mLANA Is Critical for \(\gamma\)-Herpesvirus Lymphoproliferation
JF  - PLoS PATHOGENS
N2  - Host colonization by lymphotropic \(\gamma\)-herpesviruses depends critically on expansion of viral genomes in germinal center (GC) B-cells. Myc is essential for the formation and maintenance of GCs. Yet, the role of Myc in the pathogenesis of \(\gamma\)-cherpesviruses is still largely unknown. In this study, Myc was shown to be essential for the lymphotropic \(\gamma\)-herpesvirus MuHV- 4 biology as infected cells exhibited increased expression of Myc signature genes and the virus was unable to expand in Myc defficient GC B- cells. We describe a novel strategy of a viral protein activating Myc through increased protein stability resulting in increased progression through the cell cycle. This is acomplished by modulating a physiological posttranslational regulatory pathway of Myc. The molecular mechanism involves Myc heterotypic poly- ubiquitination mediated via the viral E3 ubiquitin- ligase mLANA protein. \(EC_5S^{mLANA}\) modulates cellular control of Myc turnover by antagonizing \(SCF^{Fbw7}\) mediated proteasomal degradation of Myc, mimicking \(SCF^{\beta-TrCP}\). The findings here reported reveal that modulation of Myc is essential for \(\gamma\)-herpesvirus persistent infection, establishing a link between virus induced lymphoproliferation and disease.
KW  - latency
KW  - murine gammaherpesvirus 68
KW  - Epstein-Barr-virus
KW  - C-MYC
KW  - nuclear antigen
KW  - germinal center
KW  - B lymphocytes
KW  - protein
KW  - cells
KW  - beta-TRCP
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131227
VL  - 9
IS  - 8
ER  - 
TY  - JOUR
A1  - Stauss, Dennis
A1  - Brunner, Cornelia
A1  - Berberich-Siebelt, Friederike
A1  - Höpken, Uta E.
A1  - Lipp, Martin
A1  - Müller, Gerd
T1  - The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6
JF  - Embo Journal
N2  - Follicular T helper (Tfh) cells are key regulators of the germinal center reaction and long-term humoral immunity. Tfh cell differentiation requires the sustained expression of the transcriptional repressor Bcl6; however, its regulation in CD4\(^+\) T cells is incompletely understood. Here, we report that the transcriptional coactivator Bob1, encoded by the Pou2af1 gene, promotes Bcl6 expression and Tfh cell development. We found that Bob1 together with the octamer transcription factors Oct1/Oct2 can directly bind to and transactivate the Bcl6 and Btla promoters. Mixed bone marrow chimeras revealed that Bob1 is required for the expression of normal levels of Bcl6 and BTLA, thereby controlling the pool size and composition of the Tfh compartment in a T cell-intrinsic manner. Our data indicate that T cell-expressed Bob1 is directly involved in Tfh cell differentiation and required for mounting normal T cell-dependent B-cell responses.
KW  - follicular T helper cells
KW  - germinal center
KW  - humoral immunity
KW  - Pou2af1
KW  - T cell differentiation
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189506
VL  - 35
IS  - 8
ER  - 
TY  - JOUR
A1  - Muhammad, Khalid
A1  - Rudolf, Ronald
A1  - Pham, Duong Anh Thuy
A1  - Klein-Hessling, Stefan
A1  - Takata, Katsuyoshi
A1  - Matsushita, Nobuko
A1  - Ellenrieder, Volker
A1  - Kondo, Eisaku
A1  -  Serfling, Edgar
T1  - Induction of Short NFATc1/αA Isoform Interferes with Peripheral B Cell Differentiation
JF  - Frontiers in Immunology
N2  - In lymphocytes, immune receptor signals induce the rapid nuclear translocation of preformed cytosolic NFAT proteins. Along with co-stimulatory signals, persistent immune receptor signals lead to high levels of NFATc1/αA, a short NFATc1 isoform, in effector lymphocytes. Whereas NFATc1 is not expressed in plasma cells, in germinal centers numerous centrocytic B cells express nuclear NFATc1/αA. When overexpressed in chicken DT40 B cells or murine WEHI 231 B cells, NFATc1/αA suppressed their cell death induced by B cell receptor signals and affected the expression of genes controlling the germinal center reaction and plasma cell formation. Among those is the Prdm1 gene encoding Blimp-1, a key factor of plasma cell formation. By binding to a regulatory DNA element within exon 1 of the Prdm1 gene, NFATc1/αA suppresses Blimp-1 expression. Since expression of a constitutive active version of NFATc1/αA interfered with Prdm1 RNA expression, LPS-mediated differentiation of splenic B cells to plasmablasts in vitro and reduced immunoglobulin production in vivo, one may conclude that NFATc1/αA plays an important role in controlling plasmablast/plasma cell formation.
KW  - B cells
KW  - DT40 cells
KW  - germinal center
KW  - NFATc1
KW  - plasmablasts
KW  - plasma cells
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197501
SN  - 1664-3224
VL  - 9
IS  - 32
ER  -