Incomplete T-cell receptor–β peptides target the mitochondrion and induce apoptosis

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3530-3541 ◽  
Author(s):  
Nir Shani ◽  
Hila Rubin-Lifshitz ◽  
Yifat Peretz-Cohen ◽  
Ketty Shkolnik ◽  
Vera Shinder ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Transmembrane Domain ◽  
Apoptotic Cell ◽  
Function Analysis ◽  
Alternative Pathway ◽  
Cell Receptor ◽  
C Terminus ◽  
Specific Localization ◽  
Induced Structure

Abstract The default pathway of cell-surface T-cell receptor (TCR) complex formation, and the subsequent transport to the membrane, is thought to entail endoplasmic reticulum (ER) localization followed by proteasome degradation of the unassembled chains. We show herein an alternative pathway: short, incomplete peptide versions of TCRβ naturally occur in the thymus. Such peptides, which have minimally lost the leader sequence or have been massively truncated, leaving only the very C terminus intact, are sorted preferentially to the mitochondrion. As a consequence of the mitochondrial localization, apoptotic cell death is induced. Structure function analysis showed that both the specific localization and induction of apoptosis depend on the transmembrane domain (TMD) and associated residues at the COOH-terminus of TCR. Truncated forms of TCR, such as the short peptides that we detected in the thymus, may be products of protein degradation within thymocytes. Alternatively, they may occur through the translation of truncated mRNAs resulting from unfruitful rearrangement or from germline transcription. It is proposed that mitochondria serve as a subcellular sequestration site for incomplete TCR molecules.

The basics of mechanotransduction

2018 ◽  
Vol 11 (556) ◽  
pp. eaau2223
Author(s):  
Erin R. Williams
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Transmembrane Domain ◽  
Cell Receptor ◽  
Α Chain

Basic residues in the transmembrane domain of the T cell receptor α chain promote its association with CD3 signaling chains.

scholarly journals 9-cis retinoic acid inhibition of activation-induced apoptosis is mediated via regulation of fas ligand and requires retinoic acid receptor and retinoid X receptor activation.

1995 ◽  
Vol 15 (10) ◽  
pp. 5576-5585 ◽  
Author(s):  
R P Bissonnette ◽  
T Brunner ◽  
S B Lazarchik ◽  
N J Yoo ◽  
M F Boehm ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
T Cell ◽  
T Cell Receptor ◽  
Target Genes ◽  
Fas Ligand ◽  
Apoptotic Cell ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Retinoid Receptor ◽  
Induced Apoptosis

T-cell hybridomas, thymocytes, and T cells can be induced to undergo apoptotic cell death by activation through the T-cell receptor. This process requires macromolecular synthesis and thus gene expression, and it has been shown to be influenced by factors regulating transcription. Recently, activation, T-cell hybridomas rapidly express the Fas/CD95 receptor and its ligand, Fas ligand (FasL), which interact to transduce the death signal in the activated cell. Retinoids, the active metabolites of vitamin A, modulate expression of specific target genes by binding to two classes of intracellular receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). They are potent modulators of apoptosis in a number of experimental models, and they have been shown to inhibit activation-induced apoptosis in T-cell hybridomas and thymocytes. Particularly effective is the prototypic pan-agonist 9-cis retinoic acid (9-cis RA), which has high affinity for both RARs and RXRs. We report here that 9-cis RA inhibits T-cell receptor-mediated apoptosis in T-cell hybridomas by blocking the expression of Fas ligand following activation. This inhibition appears to be at the level of FasL mRNA, with the subsequent failure to express cell surface FasL. RAR-selective (TTNPB) or RXR-selective (LG100268) ligands alone were considerably less potent than RAR-RXR pan-agonists. However, the addition of both RAR- and RXR-selective ligands was as effective as the addition of 9-cis RA alone. The demonstrates that the inhibitory effect requires the ligand-mediated activation of both retinoid receptor signaling pathways.

scholarly journals Identification of a Phospholipase C-γ1 (PLC-γ1) SH3 Domain-Binding Site in SLP-76 Required for T-Cell Receptor-Mediated Activation of PLC-γ1 and NFAT

2001 ◽  
Vol 21 (13) ◽  
pp. 4208-4218 ◽  
Author(s):  
Deborah Yablonski ◽  
Theresa Kadlecek ◽  
Arthur Weiss
Keyword(s):  
T Cell ◽  
Phospholipase C ◽  
T Cell Receptor ◽  
Function Analysis ◽  
Cell Receptor ◽  
Sh3 Domain ◽  
Functional Domain ◽  
Rich Region ◽  
Activated T Cells ◽  
Proline Rich Region

ABSTRACT SLP-76 is an adapter protein required for T-cell receptor (TCR) signaling. In particular, TCR-induced tyrosine phosphorylation and activation of phospholipase C-γ1 (PLC-γ1), and the resultant TCR-inducible gene expression, depend on SLP-76. Nonetheless, the mechanisms by which SLP-76 mediates PLC-γ1 activation are not well understood. We now demonstrate that SLP-76 directly interacts with the Src homology 3 (SH3) domain of PLC-γ1. Structure-function analysis of SLP-76 revealed that each of the previously defined protein-protein interaction domains can be individually deleted without completely disrupting SLP-76 function. Additional deletion mutations revealed a new, 67-amino-acid functional domain within the proline-rich region of SLP-76, which we have termed the P-1 domain. The P-1 domain mediates a constitutive interaction of SLP-76 with the SH3 domain of PLC-γ1 and is required for TCR-mediated activation of Erk, PLC-γ1, and NFAT (nuclear factor of activated T cells). The adjacent Gads-binding domain of SLP-76, also within the proline-rich region, mediates inducible recruitment of SLP-76 to a PLC-γ1-containing complex via the recruitment of both PLC-γ1 and Gads to another cell-type-specific adapter, LAT. Thus, TCR-induced activation of PLC-γ1 entails the binding of PLC-γ1 to both LAT and SLP-76, a finding that may underlie the requirement for both LAT and SLP-76 to mediate the optimal activation of PLC-γ1.

Disruption of the p38aTyr323 alternative pathway prevents T cell receptor‐mediated p38aTyr323 activation in primary T cells

2008 ◽  
Vol 22 (S2) ◽  
pp. 391-391
Author(s):  
Ludmila Jirmanova ◽  
Dandapantula N. Sarma ◽  
Dragana Jankovic ◽  
Paul Mittelstadt ◽  
Jonathan D. Ashwell
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Alternative Pathway ◽  
Cell Receptor

scholarly journals Genetic disruption of p38α Tyr323 phosphorylation prevents T-cell receptor–mediated p38α activation and impairs interferon-γ production

Blood ◽  
2009 ◽  
Vol 113 (10) ◽  
pp. 2229-2237 ◽  
Author(s):  
Ludmila Jirmanova ◽  
Dandapantula N. Sarma ◽  
Dragana Jankovic ◽  
Paul R. Mittelstadt ◽  
Jonathan D. Ashwell
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Function ◽  
Alternative Pathway ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Wild Type ◽  
T Helper 1 ◽  
Ifn Γ

AbstractT cells possess a p38 activation alternative pathway in which stimulation via the antigen receptor (T-cell receptor [TCR]) induces phosphorylation of p38α and β on Tyr323. To assess the contribution of this pathway to normal T-cell function, we generated p38α knockin mice in which Tyr323 was replaced with Phe (p38αY323F). TCR-mediated stimulation failed to activate p38αY323F as measured by phosphorylation of the Thr-Glu-Tyr activation motif and p38α catalytic activity. Cell-cycle entry was delayed in TCR-stimulated p38αY323F T cells, which also produced less interferon (IFN)–γ than wild-type T cells in response to TCR-mediated but not TCR-independent stimuli. p38αY323F mice immunized with T-helper 1 (Th1)–inducing antigens generated normal Th1 effector cells, but these cells produced less IFN-γ than wild-type cells when stimulated through the TCR. Thus, the Tyr323-dependent pathway and not the classic mitogen-activated protein (MAP) kinase cascade is the physiologic means of p38α activation through the TCR and is necessary for normal Th1 function but not Th1 generation.

scholarly journals Immature thymocytes become sensitive to calcium-mediated apoptosis with the onset of CD8, CD4, and the T cell receptor expression: a role for bcl-2?

1993 ◽  
Vol 178 (5) ◽  
pp. 1745-1751 ◽  
Author(s):  
S Andjelić ◽  
N Jain ◽  
J Nikolić-Zugić
Keyword(s):  
Cell Death ◽  
T Cell ◽  
T Cell Receptor ◽  
Apoptotic Cell ◽  
Calcium Ionophore ◽  
Cell Receptor ◽  
Receptor Expression ◽  
Clonal Deletion ◽  
Induced Apoptosis ◽  
Precursor Activity

During intrathymic negative selection by clonal deletion, crosslinking of the T cell receptor (TCR) induces cell death by delivering an apoptotic signal(s) to the nucleus along a calcium-dependent pathway. We investigated the reactivity of early precursor-containing thymocytes to Ca(2+)-induced signals, and discovered a breakpoint in their sensitivity to calcium-mediated cell death (CMCD). CD25+CD8-4- TCR- (triple negative [TN]) thymocytes stimulated with a calcium ionophore maintain their viability and precursor activity. By contrast, their immediate progeny, CD25-CD8lo4loTCR alpha beta lo (triple low [TL]) cells react to calcium elevation by abrogation of precursor activity and apoptotic cell death. This developmental difference is specific for CMCD, since both CD25+TN and CD25-TL cells are susceptible to steroid-induced apoptosis. The presence of bcl-2 mRNA correlates directly to the resistance to CMCD-CD25+ TN cells express it and CD25-TL cells do not. These experiments show that thymocytes become sensitive to Ca(2+)-induced apoptosis as soon as they begin to express molecules that mediate thymic selection, and suggest that a concomitant downregulation of bcl-2 may mediate this phenomenon.

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