TCR-Induced Tyrosine Phosphorylation at Tyr270 of SUMO Protease SENP1 by Lck Modulates SENP1 Enzyme Activity and Specificity

Li, Yunyi; Cen, Haohua; Gong, Beini; Mai, Siqi; Wang, Qilong; Mou, Sisi

doi:10.3389/fcell.2021.789348

Cited by 4 publications

(3 citation statements)

References 57 publications

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“…Indeed, loss of Lck expression or activity resulted in IP 3 receptor downregulation [44]. Finally, recent data suggest that Lck interacts with SUMO-specific protease 1 (SENP1) and that SENP1 is an Lck substrate [45].…”

Section: Discussionmentioning

confidence: 99%

Y192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-γ1 and Thymic Selection

Kästle

Merten

Hartig

et al. 2022

IJMS

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Signaling via the TCR, which is initiated by the Src-family tyrosine kinase Lck, is crucial for the determination of cell fates in the thymus. Because of its pivotal role, ablation of Lck results in a profound block of T-cell development. Here, we show that, in addition to its well-known function in the initiation of TCR signaling, Lck also acts at a more downstream level. This novel function of Lck is determined by the tyrosine residue (Y192) located in its SH2 domain. Thymocytes from knock-in mice expressing a phosphomimetic Y192E mutant of Lck initiate TCR signaling upon CD3 cross-linking up to the level of PLC-γ1 phosphorylation. However, the activation of downstream pathways including Ca2+ influx and phosphorylation of Erk1/2 are impaired. Accordingly, positive and negative selections are blocked in LckY192E knock-in mice. Collectively, our data indicate that Lck has a novel function downstream of PLCγ-1 in the regulation of thymocyte differentiation and selection.

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Section: Discussionmentioning

confidence: 99%

Y192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-γ1 and Thymic Selection

Kästle

Merten

Hartig

et al. 2022

IJMS

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“…Another potential candidate by which PtpA might affect SUMOylation is SUMO-specific protease 1 (SENP1), which acts as an endopeptidase to generate mature SUMO for protein conjugation and as an isopeptidase to remove conjugated SUMO from targets ( 40 ). SENP1 was recently identified as a substrate of protein tyrosine kinase Lck, which phosphorylates SENP1 at Tyr270, thereby rendering its endopeptidase and isopeptidase activities ( 41 ). Lck was originally described as lymphocyte-specific kinase but was also found in RAW 264.7 cells ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

The secreted tyrosine phosphatase PtpA promotes Staphylococcus aureus survival in RAW 264.7 macrophages through decrease of the SUMOylation host response

Youssouf,

Martin,

Bischoff

et al. 2023

Microbiol Spectr

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Staphylococcus aureus is a human pathogen that is extremely adaptable and is the cause of a variety of nosocomial and community-acquired infectious diseases. During infection, S. aureus is able to affect the host cell in many ways to enable its own multiplication, spread, and evasion of the host immune defense. One of the mechanisms utilized by S. aureus to survive is to inhibit the SUMOylation of host proteins in order to increase its intracellular survival and persistence. Here, we show that the reduction in the levels of cellular SUMO-conjugated proteins in S. aureus strain Newman-infected RAW 264.7 cells is associated with the S. aureus secreted protein tyrosine phosphatase PtpA, which results in a reduction of ubiquitin-conjugating enzyme 9 (Ubc9) protein level, the critical enzyme of the SUMOylation modification. In addition, we demonstrate that the amino acid residue D120, which is essential for PtpA phosphatase activity, is required for this reduction. This study shows for the first time that S. aureus strain Newman impedes via PtpA the host SUMOylation response, which contributes to promoting the persistence of S. aureus within the host. IMPORTANCE Staphylococcus aureus uses numerous strategies to survive and persist in the intracellular environment of professional phagocytes, including modulation of the SUMOylation process. This study aims to understand how S. aureus alters host SUMOylation to enhance its intracellular survival in professional phagocytes. Our results indicate that S. aureus strain Newman utilizes PtpA-driven phosphorylation to decrease the amount of SUMOylated proteins in murine macrophages to facilitate its survival in this immune cell type.

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“…All experiments were performed in triplicate. The primer sequences are listed in Additional files 5 and 6 and the protocol for reverse transcription and RT-PCR is previously described [ 35 , 36 ]. The risks cores of cancer cell line are defined by the relative expression of each gene and its associated Cox coefficient: PER1 × 0.124154 + AKAP12 × 0.145457 + MMP17 × 0.122203.…”

Section: Methodsmentioning

confidence: 99%

Prognostic risk factors of serous ovarian carcinoma based on mesenchymal stem cell phenotype and guidance for therapeutic efficacy

et al. 2023

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Background Epithelial ovarian cancer is the leading cause of death from gynecologic cancer, in which serous ovarian carcinoma (SOC) is the most common histological subtype. Although PARP inhibitors (PARPi) and antiangiogenics have been accepted as maintenance treatment in SOC, response to immunotherapy of SOC patients is limited. Methods The source of transcriptomic data of SOC was from the Cancer Genome Atlas database and Gene Expression Omnibus. The abundance scores of mesenchymal stem cells (MSC scores) were estimated for each sample by xCell. Weighted correlation network analysis is correlated the significant genes with MSC scores. Based on prognostic risk model construction with Cox regression analysis, patients with SOC were divided into low- and high-risk groups. And distribution of immune cells, immunosuppressors and pro-angiogenic factors in different risk groups was achieved by single-sample gene set enrichment analysis. The risk model of MSC scores was further validated in datasets of immune checkpoint blockade and antiangiogenic therapy. In the experiment, the mRNA expression of prognostic genes related to MSC scores was detected by real-time polymerase chain reaction, while the protein level was evaluated by immunohistochemistry. Results Three prognostic genes (PER1, AKAP12 and MMP17) were the constituents of risk model. Patients classified as high-risk exhibited worse prognosis, presented with an immunosuppressive phenotype, and demonstrated high micro-vessel density. Additionally, these patients were insensitive to immunotherapy and would achieve a longer overall survival with antiangiogenesis treatment. The validation experiments showed that the mRNA of PER1, AKAP12, and MMP17 was highly expressed in normal ovarian epithelial cells compared to SOC cell lines and there was a positive correlation between protein levels of PER1, AKAP12 and MMP17 and metastasis in human ovarian serous tumors. Conclusion This prognostic model established on MSC scores can predict prognosis of patients and provide the guidance for patients receiving immunotherapy and molecular targeted therapy. Because the number of prognostic genes was fewer than other signatures of SOC, it will be easily accessible on clinic.

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TCR-Induced Tyrosine Phosphorylation at Tyr270 of SUMO Protease SENP1 by Lck Modulates SENP1 Enzyme Activity and Specificity

Cited by 4 publications

References 57 publications

Y192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-γ1 and Thymic Selection

Y192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-γ1 and Thymic Selection

The secreted tyrosine phosphatase PtpA promotes Staphylococcus aureus survival in RAW 264.7 macrophages through decrease of the SUMOylation host response

Prognostic risk factors of serous ovarian carcinoma based on mesenchymal stem cell phenotype and guidance for therapeutic efficacy

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