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LIME, a Novel Transmembrane Adaptor Protein, Mediates T Cell Activation and Immunological synapse Formation

LIME, a Novel Transmembrane Adaptor Protein, Mediates T Cell Activation and Immunological synapse Formation

In this study, we identify and characterize a novel transmembrane adaptor protein, designated LIME, as a binding partner of the Lck SH2(Src-homology 2) domain. LIME possesses a short extracellular domain, a transmembrane domain and a cytoplasmic tail containing 5 tyrosine-based motifs. The protein is primarily expressed in hematopoietic cells and lung. Interestingly, LIME expression is upregulated by TCR stimulation and sustained up to 24h suggesting that LIME acts throughout the early to late stages of T cell activation. LIME is localized to membrane rafts and distributed within the T cell-APC contact site. Upon TCR stimulation of Jurkat T cells, LIME associates with Lck as a tyrosine-phosphorylated protein. Experiments using Jurkat T cells expressing CD8-LIME chimera reveal that the protein associates with PI3K, Grb2, Gads and SHP-2, and activates ERK1/2 and JNK, but not p38. Moreover, overexpression of LIME in Jurkat T cells induces transcriptional activation of the Interleukin-2(IL-2) promoter. Our data collectively show that LIME is a raft-associated transmembrane adaptor protein linking TCR stimuli to downstream signaling pathways via associations with Lck.

Formation of the immunological synapse(IS) requires TCR signaling-mediated rearrangement of actins and subsequent enhancement of integrin-mediated adhesion. Here, we tested the possibility that LIME is involved in the TCR-mediated actin polymerization and integrin-mediated adhesion of T cells. Upon conjugation with APC, LIME colocalized with talin and Lck, markers of IS. When LIME is overexpressed, F-actin concentration at IS was markedly enhanced. In contrast, the knockdown of LIME expression by siRNA resulted in the disruption of actin polymerization and the IS formation. Furthermore, LIME asssocated with Vav upon TCR stimulation and promoted the Guanine Nucleotide Exchange factor activity of Vav. These data establish LIME as an adaptor linking TCR stimulus to actin polymerization at IS and subsequent integrin clustering.

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