Search bioRxiv⌕ Search

bioRxiv · 10.1101/481507

PTPN22 interacts with EB1 to regulate T cell receptor signaling

Abstract

PTPN22 has been reported as an important negative regulator of T cell signaling. Here we identified EB1 as an associated protein of PTPN22 via 2-hybrid and mass spectrometry screening.\n\nRecently the phosphorylation of EB1 has been proved in the regulation of T cell receptor (TCR) mediated signaling pathway. Our results shown that PTPN22 interacted with EB1 through the P1 domain of PTPN22, and regulated the Y247 phosphorylation site of EB1. The subsequent results suggest that PTPN22 interacts with EB1 and regulate the phosphorylation of EB1, which results in the regulation of the expression of T cell activation markers of CD25 and CD69, and the phosphorylation levels of the T cell signaling molecules, such as ZAP-70, LAT and Erk, ultimately resulting in NFAT transcription factors entering the nucleus and regulating the secretion of cytokine IL-2. This newly identified interaction between PTPN22 and EB1 may play an important role in TCR signal pathways.

Source connections

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Zhang, X., Bai, B., Wang, T., Zhao, J., Zhang, N., Zhao, Y., Wang, X., Wang, B., Yu, Y.. 2018-11-28. PTPN22 interacts with EB1 to regulate T cell receptor signaling. https://doi.org/10.1101/481507

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Platycodin D2 Targets Vimentin to Suppress Fibroblast-Myofibroblast Transition: A Novel Therapeutic Strategy Against Pulmonary Fibrosis

Background Pulmonary fibrosis is a progressive lung disease characterized by excessive extracellular matrix deposition and irreversible decline in lung function with limited effective therapeutic targets. Vimentin, a type III intermediate filament protein, plays a critical role in fibroblast activation and fibrogenesis, representing a promising drug target. Methods Novel vimentin ligands were screened via virtual screening. SPR assay verified compound-vimentin binding affinity. CETSA and CD spectroscopy analyzed protein structural changes after compound binding. In vitro FMT model and in vivo bleomycin-induced pulmonary fibrosis model were used to assess antifibrotic effects, and mutagenesis assays identified key binding amino acid residues. Results Platycodin D2 (PD2) from Platycodon grandiflorus was identified as a novel high-affinity vimentin ligand (Kd = 392.8 nM). PD2 binds vimentin directly, alters its secondary structure and induces insoluble aggregation. It effectively inhibits TGF-{beta}1-induced FMT in vitro and mitigates bleomycin-induced pulmonary fibrosis in vivo, reducing collagen deposition and improving animal survival. Critically, mutagenesis validation confirmed that key residues (Glu138 in chain A, Glu132 and Glu143 in chain B, as well as Glu50 and Arg54 in chain C) are essential for this interaction. Conclusions Our findings establish PD2 as a novel pharmacological inducer of aberrant vimentin aggregation, presenting a distinct target-driven strategy for antifibrotic drug development.

cell biology↗

Diversification of budding yeast polarization dynamics after compensatory experimental evolution

Essential cellular processes evolve under strong selection, yet protein networks underlying conserved functions can vary substantially. To what extent evolution constrains the intracellular dynamics of proteins performing essential functions is currently largely unknown. Here, we characterize budding yeast polarization phenotypes along a previously established evolutionary recovery trajectory, compensating for the loss of near-essential polarity gene BEM1. Through quantitative live cell imaging, we show that loss of BEM1 weakens and destabilizes polarization. Surprisingly, in recovered evolved lineages, protein dynamics change significantly compared to the ancestor: most notably, presence of main regulator Cdc42-GTP is strongly decreased, while polarisome member Spa2 localizes more slowly into mobile foci. Although separate phenotypic characteristics are only weakly constrained, we find evidence of effective protein-independent localization modes, revealing signs of convergence along the evolutionary trajectory. Together, our results show that evolution can restore global cellular function without conserving microscopic organization, instead giving rise to novel molecular phenotypes.

cell biology↗

Role of Very Long-Chain Fatty Acyl-Ceramides in Endocytic Uptake

Specialized endoplasmic reticulum (ER) subdomains termed ER sterol exit sites (ERSES), transiently contact endocytic sites to locally supply sterols, which in turn initiate actin polymerization and drive membrane invagination. Osh2, an oxysterol-binding protein (OSBP)-related protein (ORP), mediates the non-vesicular sterol transfer at ER-endocytic contact sites (ER-ECS). In search for additional ERSES components, we identified Fat1, a fatty acid (FA) transporter and acyl-CoA synthetase with specificity for very long-chain (VLC) FAs (C20-C26). Analysis of VLC-FA anabolic and catabolic pathways revealed a specific requirement for VLC fatty acyl-ceramides (VLCA-Cers) in the constriction of endocytic invaginations. Strikingly, the Cer synthase physically interacted with the endocytic machinery, pointing to a direct role of VLCFA-Cers in membrane remodelling. Consistent with this view, molecular dynamics and live-cell imaging of a Cer probe indicated that the ORPs Osh1 and Osh3 contribute to Cer export from at ER-ECS and and that their depletion recapitulates the endocytic defects observed in the absence of VLCFA-Cer. Our findings establish that local transport of VLCA-Cers is required for endocytic budding and reveal ERSES as hubs where Cer and sterol biosynthesis and transport converge

cell biology↗