T-cell activation is accompanied by an ubiquitination process occurring at the immunological synapse

Wiedemann, Aurélie; Müller, Sabina; Favier, Benoît; Penna, Doris; Guiraud, Martine; Delmas, Christelle; Champagne, Éric; Valitutti, Salvatore

doi:10.1016/j.imlet.2004.10.014

Cited by 40 publications

(34 citation statements)

References 28 publications

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“…4). Moreover, the Valitiutti group has previously demonstrated that T cell activation induces ubiquitination events at the immunological synapse (22). Thus, proapoptotic signals initiate a negative feedback loop that rapidly down-regulates the input signal by eliminating ZAP70.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of Proximal Signaling Events after TCR/CD8-Mediated Induction of Proliferation or Apoptosis in Mature CD8+ T Cells

Wang¹,

Simeoni²,

Lindquist³

et al. 2008

The Journal of Immunology

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Engagement of the TCR can induce different functional outcomes such as activation, proliferation, survival, or apoptosis. How the TCR-mediated signaling cascades generating these distinct cellular responses are organized on the molecular level is so far not completely understood. To obtain insight into this question, we analyzed TCR/CD8-mediated signaling events in mature OT-I TCR transgenic T cells under conditions of stimulation that lead to either proliferation or apoptosis. These experiments revealed major differences in the phosphorylation dynamics of LAT, ZAP70, protein kinase B, phospholipase C-γ1, protein kinase D1, and ERK1/2. Moreover, input signals leading to apoptosis induced a strong, but transient activation of ERK1/2 mainly at sites of TCR-engagement. In contrast, stimuli promoting survival/proliferation generated a low and sustained activation of ERK1/2, which colocalizes with Ras in recycling endosomal vesicles. The transient activation of ERK1/2 under pro-apoptotic conditions of stimulation is at least partially due to the rapid polyubiquitination and subsequent degradation of ZAP70, whereas the sustained activation of ERK1/2 under survival promoting conditions is paralleled by the induction/phosphorylation of anti-apoptotic molecules such as protein kinase B and Bcl-xL. Collectively, our data provide signaling signatures that are associated with proliferation or apoptosis of T cells.

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Section: Discussionmentioning

confidence: 99%

Dynamics of Proximal Signaling Events after TCR/CD8-Mediated Induction of Proliferation or Apoptosis in Mature CD8+ T Cells

Wang¹,

Simeoni²,

Lindquist³

et al. 2008

The Journal of Immunology

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“…Sustained, central clustering of TCRm arranges into a TCR-enriched domain known as the central supramolecular activation cluster (cSMAC) where TCR signaling is regulated (23,24). The massive clustering of TCRm produces a size-based exclusion of LFA-1: ICAM-1 integrin pairs from the synapse center, which arrange into a peripheral adhesion domain (or pSMAC) at the cell−cell interface (21).…”

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confidence: 99%

Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells

Céspedes

Bueno

Ramírez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Human respiratory syncytial virus (hRSV) is the leading cause of bronchiolitis and pneumonia in young children worldwide. The recurrent hRSV outbreaks and reinfections are the cause of a significant public health burden and associate with an inefficient antiviral immunity, even after disease resolution. Although several mouse-and human cell-based studies have shown that hRSV infection prevents naïve T-cell activation by antigen-presenting cells, the mechanism underlying such inhibition remains unknown. Here, we show that the hRSV nucleoprotein (N) could be at least partially responsible for inhibiting T-cell activation during infection by this virus. Early after infection, the N protein was expressed on the surface of epithelial and dendritic cells, after interacting with trans-Golgi and lysosomal compartments. Further, experiments on supported lipid bilayers loaded with peptide-MHC (pMHC) complexes showed that surface-anchored N protein prevented immunological synapse assembly by naive CD4 + T cells and, to a lesser extent, by antigen-experienced T-cell blasts. Synapse assembly inhibition was in part due to reduced T-cell receptor (TCR) signaling and pMHC clustering at the T-cell− bilayer interface, suggesting that N protein interferes with pMHC− TCR interactions. Moreover, N protein colocalized with the TCR independently of pMHC, consistent with a possible interaction with TCR complex components. Based on these data, we conclude that hRSV N protein expression at the surface of infected cells inhibits T-cell activation. Our study defines this protein as a major virulence factor that contributes to impairing acquired immunity and enhances susceptibility to reinfection by hRSV.

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“…On the other hand, heat shock protein 90 (Hsp90) prevents active p56 lck from being targeted for degradation by ubiquitination (18 -20). Recent work also suggests that TCR-induced ubiquitination occurs at the IS (21). During TCR stimulation, ubiquitinated proteins accumulate at the T cell-APC contact site (21).…”

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confidence: 99%

“…Recent work also suggests that TCR-induced ubiquitination occurs at the IS (21). During TCR stimulation, ubiquitinated proteins accumulate at the T cell-APC contact site (21).…”

mentioning

confidence: 99%

SOCS-6 Negatively Regulates T Cell Activation through Targeting p56 to Proteasomal Degradation

Choi

Son

Park

et al. 2010

Journal of Biological Chemistry

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The T cell-specific tyrosine kinase, p56 lck , plays crucial roles in T cell receptor (TCR)-mediated T cell activation. Here, we report that SOCS-6 (suppressor of cytokine signaling-6) is a negative regulator of p56 lck . SOCS-6 was identified as a protein binding to the kinase domain of p56 lck through yeast two-hybrid screening. SOCS-6 bound specifically to p56 lck (F505), which mimics the active form of p56 lck , but not to wild type p56 lck . In Jurkat T cells, SOCS-6 binding to p56 lck was detected 1-2 h after TCR stimulation. Confocal microscopy showed that upon APC-T cell conjugation, SOCS-6 was recruited to the immunological synapse and colocalized with the active form of p56 lck . SOCS-6 promoted p56lck ubiquitination and its subsequent targeting to the proteasome. Moreover, SOCS-6 overexpression led to repression of TCR-dependent interleukin-2 promoter activity. These results establish that SOCS-6 acts as a negative regulator of T cell activation by promoting ubiquitin-dependent proteolysis.The T lymphocyte-specific member of the Src-type tyrosine kinase family, p56 lck , plays essential roles in development, antigen-induced T cell activation, and proliferation (1-3). During TCR 4 -mediated T cell activation, p56 lck is activated and transmits a positive signal by interacting with CD4/CD8 (4, 5). Upon engagement of the antigen-major histocompatibility complex with TCR-CD4-CD8 complexes, p56 lck phosphorylates the immunoreceptor tyrosine-based activation motifs of the CD3 -chain and provides the binding site for ZAP-70 tyrosine kinase (6). Subsequent ZAP-70 activation leads to phosphorylation of signaling proteins, including LAT, and amplification of TCR-mediated signaling (7,8). In this process, p56 lck migrates to T cell-APC contact regions known as immunological synapses (IS) and thereby enhances TCR signaling (9, 10). Given the importance of p56 lck function in T cell activation, establishing how p56 lck activity is regulated is essential to understand that activation.The structure of p56 lck is similar to that of other Src family kinases and exhibits the following common domains: N-terminal attachment sites for saturated fatty acid addition, a unique region; an Src homology 3 (SH3) domain; an SH2 domain; a tyrosine kinase domain (SH1); and a C-terminal negative regulatory site, tyrosine 505 (Tyr-505) (11). p56 lck kinase activity is regulated by intramolecular interactions through its regulatory domains and/or phosphorylation (11). For example, phosphorylation of Tyr-394 in the activation loop of the kinase domain increases enzymatic activity, whereas phosphorylation of Tyr-505 renders the enzyme less active. Phosphorylated Tyr-505 interacts with its own SH2 domain, promoting a closed conformation and maintaining the kinase in an inactive state (12). Phenylalanine substitution of the regulatory tyrosine residue (Y505F) results in a constitutively active form of the protein.The status of the regulatory tyrosine is maintained both by a kinase, Csk, which phosphorylates it (13), and by a transmembrane...

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T-cell activation is accompanied by an ubiquitination process occurring at the immunological synapse

Cited by 40 publications

References 28 publications

Dynamics of Proximal Signaling Events after TCR/CD8-Mediated Induction of Proliferation or Apoptosis in Mature CD8+ T Cells

Dynamics of Proximal Signaling Events after TCR/CD8-Mediated Induction of Proliferation or Apoptosis in Mature CD8+ T Cells

Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells

SOCS-6 Negatively Regulates T Cell Activation through Targeting p56 to Proteasomal Degradation

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