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PTPN22 Interacts with EB1 to Regulate T Cell Receptor Signaling

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PTPN22 Interacts with EB1 to Regulate T Cell Receptor Signaling bioRxiv preprint doi: https://doi.org/10.1101/481507; this version posted November 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. PTPN22 interacts with EB1 to regulate T cell receptor signaling Xiaonan Zhang, Bin Bai, Tao Wang, Jiahui Zhao, Na Zhang, Yanjiao zhao, Xipeng Wang, Yang Yu*, Bing Wang* Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang, 110819, P. R. China * Corresponding author: Bing Wang, Ph. D., Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang, 110169, P. R. China Phone: (+86)2483656125, Fax: (+86)2483656125, E-mail: [email protected] Yang Yu, Ph. D., Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang, 110169, P. R. China Phone: (+86)2483656116, E-mail: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/481507; this version posted November 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 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. Recently 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. Key words EB1/PTPN22/Protein interactions/phosphorylation/TCR bioRxiv preprint doi: https://doi.org/10.1101/481507; this version posted November 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Introduction Protein tyrosine phosphatases (PTPs) are essential signal transduction enzymes that mediate the immune response [1]. Inheritance of a coding variant of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is associated with increased susceptibility to autoimmunity and infection [2, 3]. The PTPN22 gene is located on the short arm of chromosome 1 (1p 13.3-lp l3.1) and encodes Lyp/Pep protein tyrosine phosphatase, which is mainly expressed in lymphocytes to inhibit the functions of T and B cells. The 802-residue of PTPN22 protein structure contains an N-terminal canonical phosphatase domain, and the five C-terminal proline, glutamic/aspartic acid, serine, threonine (PEST)-containing sequences [4]. During recent years, PTPN22 has been reported as a negative regulator of the TCR signaling pathway. For example, PTPN22 is involved in PTPN22-Csk interactions, which causes the activation of tyrosine kinase Csk to phosphorylate the inhibitory tyrosine sites on Lck and Fyn of the Src family tyrosine kinases, while four proline-rich regions of PTPN22 act as mediates by binding to the Src homology 3 (SH3) domain of the Csk tyrosine kinase [5-10]. The human PTPN22 gene encoding Lyp has been associated with a number of autoimmune diseases including rheumatoid arthritis [11-13], Type I diabetes [12, 14], Graves’ disease [15], and systemic lupus erythematosus [16]. End-binding proteins (EBs) are highly conserved and ubiquitous plus-end tracking proteins (+TIP) [17]. The N-terminal calponin homology (CH) domain of EB1, EB2 and EB3 is able to bind to MTs. The C-terminus of EBs have a flexible acidic tail that contains the sequence EEY/F, which is required for self-inhibition and binding to various partners, and can also control MT growth [18, 19]. End-binding protein 1 (EB1) is a member of microtubule +TIP, which bind to the plus ends of growing MTs via its conserved calponin-homology domain [20]. EB1 regulates MT stability at bundled actin-rich sites of the cell cortex through the recruitment of other +TIPs, such as SxIP motif-containing proteins and cytoskeleton-associated glycine-rich domain (CAP-Gly) containing proteins, to MT plus ends [21, 22] or by coordinating with other MT-binding proteins such as adenomatous polyposis coli (APC), CLASPs, MT-actin crosslinking factor 1 (MACF1)/actin crosslinking family 7 (ACF7), and mitotic centromere associated kinesin (MCAK) bioRxiv preprint doi: https://doi.org/10.1101/481507; this version posted November 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. [23-25]. EB1 plays an important role in the regulation of microtubule dynamics and has been implicated in many autoimmune diseases [26, 27]. Post translational modification of EB1 especially through phosphorylation and dephosphorylation is very important for the normal function of EB1 proteins. Recently, EB1 was found to bind to the CD3 ITAMs and also regulate vesicular trafficking at the IS, and therefore is the connection between the TCR and downstream signaling molecules [28]. Ran et al. reported that the phosphorylation of EB1 regulates the recruitment of CLIP-170 and p150 to the plus ends of astral microtubules [29]. However, to date, there are no PTPs have been identified to associate with or regulate the phosphorylation levels of EB1. Herein, we identified EB1 as an associated protein of PTPN22 via 2-hybrid and mass spectrometry screening. Our results shown that PTPN22 interacted with EB1 through the P1 domain of PTPN22, and regulated the Y247 phosphorylation site 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 the secretion of cytokine IL-2. This newly identified interaction between PTPN22 and EB1 may play an important role in TCR signal pathways. RESULTS PTPN22 interacts with EB1 in vitro and in vivo Virtually all processes in living cells are dependent on protein-protein interactions (PPIs). The most frequently used powerful genetic systems for mapping PPIs are the yeast two-hybrid (Y2H) screen and mass spectrometry analysis. In this study, yeast two-hybrid screens were performed to screen a mouse hematopoietic cells cDNA library [30]. The carboxy-terminal domain of PTPN22601-802 was employed as a bait to screen potential proteins which may interact with PTPN22. About 50 positive colonies had grown from one million transfectants, and the EB1 were one of the top candidates among the selected colonies (Figure 1A). Interestingly the EB1 was also identified as a binding partner of PTPN22 via mass spectrometry analysis (Figure 1B, EV1). To test the physical interaction between PTPN22 and EB1, we performed a GST pull-down assay in vitro (Figure 1C, EV2), and found that His-EB1 was pulled down with the immunoprecipitate of GST-PTPN22, suggesting the possibility that PTPN22 can interact with EB1 in vitro. In addition, bioRxiv preprint doi: https://doi.org/10.1101/481507; this version posted November 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Flag-PTPN22 was verified to associate with EB1 by a co-immunoprecipitation (CO-IP) assay of an overexpression system in 293T cells (Figure 1D), then the interaction between endogenous PTPN22 and EB1 was performed in BI-141, Jurket and RAW264.7 cell lines was studied with the use of CO-IP assays, with the results showing that endogenous PTPN22 and EB1 proteins may form a complex (Figure 1E, F, G). Subsequently, the interaction between PTPN22 (Green fluorescence protein) and EB1 (Red fluorescence protein) was also confirmed in Jurket cells and RAW264.7 cells through the cell co-localization assay (Figure 1H, I). Identifiion of the binding sites between PTPN22 and EB1 In order to identify the interaction sites between PTPN22 and EB1, the PTPN22 gene was divided into different fragments according to its the secondary protein structure of PTPN22 (PTPN22-Flag ΔC1, PTPN22-Flag ΔC2, PTPN22-Flag ΔC3, PTPN22-Flag ΔN1, PTPN22-Flag ΔN2 andPTPN22-Flag ΔN3) (Figure 2A). These fragments were transfected into 293T cells respectively. The association between Flag tagged PTPN22 fragments and endogenous EB1 were studied using CO-IP. As a results, PTPN22-Flag ΔC2, PTPN22-Flag ΔC3 and PTPN22-Flag ΔN1 can interact with EB1 (Figure 2C). Since these three fragments have a common P1 domain we constructed a P1 domain deleted PTPN22 mutant (PTPN22-Flag ΔP1) (Figure 2B). As shown in figure 2D PTPN22-Flag WT can interact with EB1 whereas PTPN22-Flag ΔP1 lost the binding features to EB1, which proving that P1 is the domain of PTPN22 to associate with EB1. Next the binding sites of EB1 need to be clarified. Figure 3A dipicts the structural model of EB1. It was reported that Tyr217 and Tyr247 of EB1 was the potential sites of the tyrosine phosphorylation, and that coiled-coil and EBH region are the site through which EB1 interacts with other molecules [31-33]. Here we constructed HA-EB1 Y217F, HA-EB1 Y217D, HA-EB1 Y247F, HA-EB1 Y247D to identify the binding sites of EB1 to PTPN22, and found that the HA-EB1 Y217F will not affect the interaction to PTPN22, while HA-EB1 Y247F/HA-EB1 Y247D decrease the binding to PTPN22 compared with EB1 WT.
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