scholarly journals CBAP promotes thymocyte negative selection by facilitating T-cell receptor proximal signaling

2014 ◽  
Vol 5 (11) ◽  
pp. e1518-e1518 ◽  
Author(s):  
K-C Ho ◽  
Y-J Chiang ◽  
A C-Y Lai ◽  
N-S Liao ◽  
Y-J Chang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Negative Selection ◽  
Cell Receptor ◽  
Proximal Signaling

scholarly journals Comparison of T Cell Receptor-Induced Proximal Signaling and Downstream Functions in Immortalized and Primary T Cells

PLoS ONE ◽  
2009 ◽  
Vol 4 (5) ◽  
pp. e5430 ◽  
Author(s):  
Rebekah R. Bartelt ◽  
Noemi Cruz-Orcutt ◽  
Michaela Collins ◽  
Jon C. D. Houtman
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Proximal Signaling

scholarly journals Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor–induced Nur77 expression and apoptosis

2005 ◽  
Vol 201 (5) ◽  
pp. 793-804 ◽  
Author(s):  
Franck Dequiedt ◽  
Johan Van Lint ◽  
Emily Lecomte ◽  
Viktor Van Duppen ◽  
Thomas Seufferlein ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
T Cell Receptor ◽  
Nuclear Export ◽  
Histone Deacetylases ◽  
Negative Selection ◽  
Cell Receptor ◽  
Protein Kinase D ◽  
Orphan Nuclear Receptor ◽  
Nuclear Exclusion

The molecular basis of thymocyte negative selection, a crucial mechanism in establishing central tolerance, is not yet resolved. Histone deacetylases (HDACs) have emerged as key transcriptional regulators in several major developmental programs. Recently, we showed that the class IIa member, HDAC7, regulates negative selection by repressing expression of Nur77, an orphan nuclear receptor involved in antigen-induced apoptosis of thymocytes. Engagement of the T cell receptor (TCR) alleviates this repression through phosphorylation-dependent nuclear exclusion of HDAC7. However, the identity of the TCR-activated kinase that phosphorylates and inactivates HDAC7 was still unknown. Here, we demonstrate that TCR-induced nuclear export of HDAC7 and Nur77 expression is mediated by activation of protein kinase D (PKD). Indeed, active PKD stimulates HDAC7 nuclear export and Nur77 expression. In contrast, inhibition of PKD prevents TCR-mediated nuclear exclusion of HDAC7 and associated Nur77 activation. Furthermore, we show that HDAC7 is an interaction partner and a substrate for PKD. We identify four serine residues in the NH2 terminus of HDAC7 as targets for PKD. More importantly, a mutant of HDAC7 specifically deficient in phosphorylation by PKD, inhibits TCR-mediated apoptosis of T cell hybridomas. These findings indicate that PKD is likely to play a key role in the signaling pathways controlling negative selection.

Antigen-induced apoptosis in developing t cells: a mechanism for negative selection of the t cell receptor repertoire*

1989 ◽  
Vol 19 (11) ◽  
pp. 2175-2177 ◽  
Author(s):  
Eric J. Jenkinson ◽  
Rosetta Kingston ◽  
Christopher A. Smith ◽  
Gwynn T. Williams ◽  
John J. T. Owen
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Negative Selection ◽  
Cell Receptor ◽  
Receptor Repertoire ◽  
Induced Apoptosis ◽  
T Cell Receptor Repertoire ◽  
Cell Receptor Repertoire ◽  
Selection Of

scholarly journals Association with PAK2 Enables Functional Interactions of Lentiviral Nef Proteins with the Exocyst Complex

mBio ◽  
2015 ◽  
Vol 6 (5) ◽  
Author(s):  
Andrea Imle ◽  
Libin Abraham ◽  
Nikolaos Tsopoulidis ◽  
Bernard Hoflack ◽  
Kalle Saksela ◽  
...  
Keyword(s):  
T Cell ◽  
Host Cell ◽  
T Cell Receptor ◽  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Molecular Surface ◽  
Actin Dynamics ◽  
Immunodeficiency Virus ◽  
Proximal Signaling

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) Nef enhances virus replication and contributes to immune evasionin vivo, but the underlying molecular mechanisms remain incompletely defined. Nef interferes with host cell actin dynamics to restrict T lymphocyte responses to chemokine stimulation and T cell receptor engagement. This relies on the assembly of a labile multiprotein complex including the host kinase PAK2 that Nef usurps to phosphorylate and inactivate the actin-severing factor cofilin. Components of the exocyst complex (EXOC), an octameric protein complex involved in vesicular transport and actin remodeling, were recently reported to interact with Nef via the same molecular surface that mediates PAK2 association. Exploring the functional relevance of EXOC in Nef-PAK2 complex assembly/function, we found Nef-EXOC interactions to be specifically mediated by the PAK2 interface of Nef, to occur in infected human T lymphocytes, and to be conserved among lentiviral Nef proteins. In turn, EXOC was dispensable for direct downstream effector functions of Nef-associated PAK2. Surprisingly, PAK2 was essential for Nef-EXOC association, which required a functional Rac1/Cdc42 binding site but not the catalytic activity of PAK2. EXOC was dispensable for Nef functions in vesicular transport but critical for inhibition of actin remodeling and proximal signaling upon T cell receptor engagement. Thus, Nef exploits PAK2 in a stepwise mechanism in which its kinase activity cooperates with an adaptor function for EXOC to inhibit host cell actin dynamics.IMPORTANCEHuman immunodeficiency virus type 1 (HIV-1) Nef contributes to AIDS pathogenesis, but the underlying molecular mechanisms remain incompletely understood. An important aspect of Nef function is to facilitate virus replication by disrupting T lymphocyte actin dynamics in response to stimulation via its association with the host cell kinase PAK2. We report here that the molecular surface of Nef for PAK2 association also mediates interaction of Nef with EXOC and establish that PAK2 provides an essential adaptor function for the subsequent formation of Nef-EXOC complexes. PAK2 and EXOC specifically cooperate in the inhibition of actin dynamics and proximal signaling induced by T cell receptor engagement by Nef. These results establish EXOC as a functionally relevant Nef interaction partner, emphasize the suitability of the PAK2 interaction surface for future therapeutic interference with Nef function, and show that such strategies need to target activity-independent PAK2 functions.

Sign in / Sign up

Export Citation Format

Share Document