مورد إلكتروني
PP2Ac/STRN4 negatively regulates STING-type I IFN signaling in tumor-associated macrophages.
| العنوان: | PP2Ac/STRN4 negatively regulates STING-type I IFN signaling in tumor-associated macrophages. |
|---|---|
| المؤلفون: | Ho, Winson S |
| المصدر: | The Journal of clinical investigation; vol 133, iss 6, e162139; 0021-9738 |
| بيانات النشر: | eScholarship, University of California 2023-03-01 |
| تفاصيل مُضافة: | Ho, Winson S Mondal, Isha Xu, Beisi Das, Oishika Sun, Raymond Chiou, Pochin Cai, Xiaomin Tahmasebinia, Foozhan McFadden, Elizabeth Wu, Caren Yu-Ju Wu, Zhihao Matsui, William Lim, Michael Meng, Zhipeng Lu, Rongze Olivia |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | Stimulator of IFN genes type I (STING-Type I) IFN signaling in myeloid cells plays a critical role in effective antitumor immune responses, but STING agonists as monotherapy have shown limited efficacy in clinical trials. The mechanisms that downregulate STING signaling are not fully understood. Here, we report that protein phosphatase 2A (PP2A), with its specific B regulatory subunit Striatin 4 (STRN4), negatively regulated STING-Type I IFN in macrophages. Mice with macrophage PP2A deficiency exhibited reduced tumor progression. The tumor microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that Hippo kinase MST1/2 was required for STING activation. STING agonists induced dissociation of PP2A from MST1/2 in normal macrophages, but not in tumor conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of Hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. In human patients with glioblastoma (GBM), YAP/TAZ was highly expressed in tumor-associated macrophages but not in nontumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized tumor-conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4-YAP/TAZ has, in our opinion, been an unappreciated mechanism that mediates immunosuppression in tumor-associated macrophages, and targeting the PP2A/STRN4-YAP/TAZ axis can sensitize tumors to immunotherapy. |
| مصطلحات الفهرس: | Macrophages, Animals, Humans, Mice, Glioblastoma, Calmodulin-Binding Proteins, Interferon Type I, Signal Transduction, Protein Processing, Post-Translational, Tumor Microenvironment, Tumor-Associated Macrophages, Cancer immunotherapy, Immunology, Oncology, Cancer, Brain Cancer, Immunization, Rare Diseases, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Medical and Health Sciences, article |
| URL: | |
| الإتاحة: | Open access content. Open access content public |
| ملاحظة: | application/pdf The Journal of clinical investigation vol 133, iss 6, e162139 0021-9738 |
| أرقام أخرى: | CDLER oai:escholarship.org:ark:/13030/qt51m901cm qt51m901cm https://escholarship.org/uc/item/51m901cmTest https://escholarship.orgTest/ 1391582927 |
| المصدر المساهم: | UC MASS DIGITIZATION From OAIster®, provided by the OCLC Cooperative. |
| رقم الانضمام: | edsoai.on1391582927 |
| قاعدة البيانات: | OAIster |
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