Serine 165 Phosphorylation of SHARPIN regulates the Activation of NF-κB

AbstractThe adaptor SHARPIN composes, together with the E3 ligases HOIP and HOIL1, the linear ubiquitin chain assembly complex. This enzymatic complex catalyzes and stamps atypical linear ubiquitin chains onto substrates to modify their fate, and has been linked to the regulation of the NF-κB pathway downstream most immunoreceptors, inflammation and cell death. However, how this signaling complex is regulated is not fully understood. Here, we report that a portion of SHARPIN is constitutively phosphorylated on the serine in position 165 in lymphoblastoid cells, and can be further induced following antigen receptor stimulation. Analysis of a phosphorylation-resistant mutant of SHARPIN revealed that this mark is dispensable for the generation of linear ubiquitin chains. However, phosphorylation allows the optimal activation of NF-κB in response to TNFα and T-cell receptor engagement. These results identify a new layer of regulation of the LUBAC, and unveil new strategies to modulate its action.

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Faculty Opinions recommendation of Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.723619637.793515738 ◽

2016 ◽

Author(s):

Miguel Vicente-Manzanares

Keyword(s):

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

T Cell Receptor ◽

Cell Receptor ◽

Receptor Signaling ◽

Programmed Cell Death 1 ◽

T Cell Receptor Signaling ◽

Cell Receptor Signaling

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Phosphorylation of multiple CD3 zeta tyrosine residues leads to formation of pp21 in vitro and in vivo. Structural changes upon T cell receptor stimulation.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)50741-4 ◽

1992 ◽

Vol 267 (5) ◽

pp. 3375-3381 ◽

Cited By ~ 2

Author(s):

S Koyasu ◽

D.J. McConkey ◽

L.K. Clayton ◽

S Abraham ◽

B Yandava ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Structural Changes ◽

Cell Receptor ◽

Receptor Stimulation ◽

Tyrosine Residues

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T cell receptor-dependent cell death of T cell hybridomas mediated by the CD30 cytoplasmic domain in association with tumor necrosis factor receptor-associated factors.

Journal of Experimental Medicine ◽

10.1084/jem.183.2.669 ◽

1996 ◽

Vol 183 (2) ◽

pp. 669-674 ◽

Cited By ~ 115

Author(s):

S Y Lee ◽

C G Park ◽

Y Choi

Keyword(s):

Cell Death ◽

T Cell ◽

Tumor Necrosis Factor ◽

T Cell Receptor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Cell Receptor ◽

Cytoplasmic Domain ◽

Activated T Cells ◽

Necrosis Factor

CD30 is a member of the tumor necrosis factor superfamily and a surface marker for Hodgkin's disease. Normal activated T cells and several virally transformed T or B cell lines also show CD30 expression. The interaction of CD30 with its ligand induces cell death or proliferation, depending on the cell type. In this report we characterize the signals mediated by the intracellular domain of CD30 and show that, in combination with signal(s) transduced by the T cell receptor, the multimerization of CD30 cytoplasmic domain induces Fas(CD95)-independent cell death in T cell hybridomas. Deletion analysis shows that the COOH-terminal 66 amino acids of CD30 are required to induce cell death. Using the yeast two-hybrid system, we have identified that the same region of CD30 interacts with tumor necrosis factor receptor-associated factor (TRAF)1 and TRAF2. These results indicate that TRAF1 and/or TRAF2 play an important role in cell death in addition to their previously identified roles in cell proliferation.

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T cell receptor for antigen induces linker for activation of T cell–dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2

Journal of Experimental Medicine ◽

10.1084/jem.20060650 ◽

2006 ◽

Vol 203 (11) ◽

pp. 2509-2518 ◽

Cited By ~ 82

Author(s):

Shen Dong ◽

Béatrice Corre ◽

Eliane Foulon ◽

Evelyne Dufour ◽

André Veillette ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Critical Role ◽

Adaptor Proteins ◽

Cell Receptor ◽

Negative Control ◽

Inositol Polyphosphate ◽

Tcr Signaling ◽

Signaling Complex ◽

Src Homology 2 Domain

Adaptor proteins positively or negatively regulate the T cell receptor for antigen (TCR) signaling cascade. We report that after TCR stimulation, the inhibitory adaptor downstream of kinase (Dok)-2 and its homologue Dok-1 are involved in a multimolecular complex including the lipid phosphatase Src homology 2 domain–containing inositol polyphosphate 5′-phosphatase (SHIP)-1 and Grb-2 which interacts with the membrane signaling scaffold linker for activation of T cells (LAT). Knockdown of LAT and SHIP-1 expression indicated that SHIP-1 favored recruitment of Dok-2 to LAT. Knockdown of Dok-2 and Dok-1 revealed their negative control on Akt and, unexpectedly, on Zap-70 activation. Our findings support the view that Dok-1 and -2 are critical elements of a LAT-dependent negative feedback loop that attenuates early TCR signal. Dok-1 and -2 may therefore exert a critical role in shaping the immune response and as gatekeepers for T cell tolerance.

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