Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells

Morra, Massimo; Lu, Jun; Poy, Florence; Martín, Margarita; Sayós, Joan; Calpe, Silvia; PhD, Charles A. Gullo; Howie, Duncan; Rietdijk, Svend; Thompson, Andrew J.; Coyle, Anthony J.; Denny, Christopher T.; Yaffe, Michael B.; Engel, Pablo; Eck, Michael J.; Terhorst, Cox

doi:10.1093/emboj/20.21.5840

Cited by 135 publications

(138 citation statements)

References 52 publications

Supporting

Mentioning

129

Contrasting

Unclassified

Order By: Relevance

“…EAT-2A is mainly expressed in natural killer cells (but also in B cells, mast cells and macrophages) and has been shown to inhibit natural killer-cell function through tyrosine phosphorylation. 31,32 In fact, Sh2d1b-deficient mice (EAT-2A À/À ) exhibited enhanced natural killer-cell cytotoxicity as well as increased IFN-g secretion upon stimulation with anti-CD16, NKG2D, Ly49D and CD224. 32 Notably, Sh2d1b is highly polymorphic with at least 76 known single nucleotide polymorphisms in various mouse strains, increasing the likelihood that polymorphisms between B6 and NZB mice exist.…”

Section: Discussionmentioning

confidence: 99%

The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus

Landolt-Marticorena

Lajoie

et al. 2011

Genes Immun

View full text Add to dashboard Cite

Lupus susceptibility loci on chromosome 1 have an important role in the development of autoimmunity in the New Zealand Black (NZB) mouse. We have previously shown that C57BL/6 congenic mice with an introgressed homozygous NZB chromosome 1 interval extending from B35 to 106 cM develop anti-nuclear antibodies and mild glomerulonephritis. In this study, we produced subcongenic mouse strains to localize the susceptibility loci in this interval and investigate how they promote autoimmunity. Our results indicate at least four susceptibility alleles and a suppressor allele. One allele is located in the 96-100 cM region and is sufficient to breach tolerance to chromatin. Addition of a second locus in the 88-96 cM interval enhances anti-dsDNA antibody production and promotes renal disease, which together with a third susceptibility allele in the 70-88 interval results in significant mortality. We further demonstrate the presence of a suppressor locus in the 35-70 or 100-102 cM interval that abrogates these phenotypes and an additional susceptibility allele in the 102-106 cM interval that restores a milder autoimmune phenotype. Several of these loci alter T-cell function. Thus, there is substantial genetic complexity in the NZB 35-106 cM interval, with disease reflecting a balance between susceptibility and suppressor loci.

show abstract

Section: Discussionmentioning

confidence: 99%

The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus

Landolt-Marticorena

Lajoie

et al. 2011

Genes Immun

View full text Add to dashboard Cite

show abstract

“…To focus on the most relevant target residues of the SAP molecule, we took advantage of the fact that EAT-2 and SAP SH2 domains share a similar overall structure and 47% amino acid identity, and are expected to bind to the same set of SLAMF ITSMs (11). As shown in Fig.…”

Section: Sap Is Required For Optimal T-b Adhesion Soon After Ligand Rmentioning

confidence: 99%

SAP-Regulated T Cell–APC Adhesion and Ligation-Dependent and -Independent Ly108–CD3ζ Interactions

Chu

Wang

Zhang

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

The germinal center response requires cooperation between Ag-specific T and B lymphocytes, which takes the form of long-lasting cell–cell conjugation in vivo. Signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) is required for stable cognate T–B cell conjugation, whereas SLAM family transmembrane (TM) receptor Ly108 may negatively regulate this process. We show that, other than phosphotyrosine-binding, SAP does not harbor motifs that recruit additional signaling intermediates to stabilize T–B adhesion. Ly108 dampens T cell adhesion to not only Ag-presenting B cells, but also dendritic cells by inhibiting CD3ζ phosphorylation through two levels of regulated Ly108–CD3ζ interactions. Constitutively associated with Src homology 2 domain–containing tyrosine phosphatase-1 even in SAP-competent cells, Ly108 is codistributed with the CD3 complex within a length scale of 100–200 nm on quiescent cells and can reduce CD3ζ phosphorylation in the absence of overt TCR stimulation or Ly108 ligation. When Ly108 is engaged in trans during cell–cell interactions, Ly108–CD3ζ interactions are promoted in a manner that uniquely depends on Ly108 TM domain, leading to more efficient CD3ζ dephosphorylation. Whereas replacement of the Ly108 TM domain still allows the constitutive, colocalization-dependent inhibition of CD3ζ phosphorylation, it abrogates the ligation-dependent Ly108–CD3ζ interactions and CD3ζ dephosphorylation, and it abolishes the suppression on Ag-triggered T–B adhesion. These results offer new insights into how SAP and Ly108 antagonistically modulate the strength of proximal TCR signaling and thereby control cognate T cell–APC interactions.

show abstract

“…Previous work showed that SLAM/SLAM interactions inhibit production of IL-12 and IL-6 by CD40L-activated DC (10). EAT-2 interacts with p-SLAM family receptors, such as CD84, CD150, LY9, and CD244, in immune cells and has been shown to be a negative regulator of cellular activation downstream of the SLAM receptor 2B4 in NK cells (11)(12)(13). Therefore, we questioned whether one of the mechanisms by which reduced EAT-2 leads to enhanced cytokine production was through impaired negative regulation of CD40 stimulation in DC.…”

Section: Resultsmentioning

confidence: 99%

Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling

Talaei

Tao

Manion

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

We showed previously that C57BL/6 congenic mice with an introgressed homozygous 70 cM (125.6 Mb) to 100 cM (179.8 Mb) interval on c1 from the lupus-prone New Zealand Black (NZB) mouse develop high titers of antinuclear Abs and severe glomerulonephritis. Using subcongenic mice, we found that a genetic locus in the 88–96 cM region was associated with altered dendritic cell (DC) function and synergized with T cell functional defects to promote expansion of pathogenic proinflammatory T cell subsets. In this article, we show that the promoter region of the NZB gene encoding the SLAM signaling pathway adapter molecule EWS-activated transcript 2 (EAT-2) is polymorphic, which results in an ∼70% reduction in EAT-2 in DC. Silencing of the EAT-2 gene in DC that lacked this polymorphism led to increased production of IL-12 and enhanced differentiation of T cells to a Th1 phenotype in T cell–DC cocultures, reproducing the phenotype observed for DC from congenic mice with the NZB c1 70–100 cM interval. SLAM signaling was shown to inhibit production of IL-12 by CD40L-activated DCs. Consistent with a role for EAT-2 in this inhibition, knockdown of EAT-2 resulted in increased production of IL-12 by CD40-stimulated DC. Assessment of downstream signaling following CD40 cross-linking in the presence or absence of SLAM cross-linking revealed that SLAM coengagement blocked activation of p38 MAPK and JNK signaling pathways in DC, which was reversed in DC with the NZB EAT-2 allele. We conclude that EAT-2 negatively regulates cytokine production in DC downstream of SLAM engagement and that a genetic polymorphism that disturbs this process promotes the development of lupus.

show abstract

Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells

Cited by 135 publications

References 52 publications

The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus

The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus

SAP-Regulated T Cell–APC Adhesion and Ligation-Dependent and -Independent Ly108–CD3ζ Interactions

Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling

Contact Info

Product

Resources

About