Abstract
The SUMO modification system plays an important role in T cell activation, yet how sumoylation regulates TCR-proximal signaling remains largely unknown. We show here that Phospholipase C-γ1 (PLC-γ1) is conjugated by SUMO1 at K54 and K987 upon TCR stimulation and that K54 sumoylation is pivotal for PLC-γ1-mediated T cell activation. We further demonstrate that TCR-induced K54 sumoylation of PLC-γ1 significantly promotes the formation of PLC-γ1 microclusters and the association of PLC-γ1 with the adaptor proteins SLP76 and Gads, but only slightly affects the phosphorylation of PLC-γ1 on Y783, which determines the enzyme catalytic activity. Moreover, upon TCR stimulation, the SUMO E3 ligases PIASxβ and PIAS3 both interact with PLC-γ1 and cooperate to sumoylate PLC-γ1, facilitating the assembly of PLC-γ1 microclusters. Together, our findings reveal a critical role of PLC-γ1 K54 sumoylation in PLC-γ1 microcluster assembly that controls PLC-γ1-mediated T cell activation, suggesting that sumoylation may have an important role in the microcluster assembly of TCR-proximal signaling proteins.
Highlights
TCR signaling controls the adaptive immune response
We demonstrated that Phospholipase C-γ1 (PLC-γ1) is sumoylated predominantly at K54 upon TCR stimulation and that PIASxβ and PIAS3 are the important SUMO E3 ligases for PLC-γ1
Our investigation revealed a novel mechanism of PLC-γ1 activation, and our results imply that sumoylation controls the assembly of PLC-γ1 membrane microclusters in TCR-proximal signaling
Summary
TCR signaling controls the adaptive immune response. TCR signaling is initiated by ligation of the TCR and its coreceptors (e.g., CD28, CD4, and CD8) by cognate antigens bound to MHC molecules (pMHC) presented by antigen-presenting cells. TCR ligation triggers phosphorylation of ITAMs (immunoreceptor tyrosine-based activation motifs) on CD3 and the ζ-chains of the TCR complex by Lck (lymphocyte-specific protein tyrosine kinase) [1, 2]. The phosphorylated ITAM tyrosines serve as docking sites to recruit and activate Zap (ζ chain of TCR-associated tyrosine kinases of 70 kD), which phosphorylates the adaptor protein LAT (linker for activation of T cells), a plasma membrane-localized adaptor protein, at multiple tyrosines [3, 4]. Tyrosinephosphorylated LAT associates with multiple proteins, such as PLC-γ1 (phospholipase C-γ1) and Gads (Grb2-related adaptor downstream of Shc). Following TCR ligation, tyrosine kinase ITK (interleukin-2-inducible T-cell kinase) is recruited to PIP3-rich membranes in which ITK interacts with the SLP76/LAT complex and is activated by Lck; the activated ITK interacts
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