Nuclear PTEN enhances the maturation of a microRNA regulon to limit MyD88-dependent susceptibility to sepsis
| Autor: | Sonia Jancar, Charles S. Dela Cruz, Flavia Sisti, Soujuan Wang, Sarah M. Sturgeon, C. Henrique Serezani, Hector R. Wong, Young Min Son, Nathaniel Andrews, José C. Alves-Filho, Lindsey D. Mayo, Fernando Q. Cunha, Stephanie L. Brandt, Nicole L. Glosson-Byers, Luciano Filgueiras |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_treatment Inflammation Biology Regulon Biochemistry Article Sepsis 03 medical and health sciences RNA interference microRNA medicine Animals Humans Tensin PTEN Molecular Biology Cell Nucleus Mice Knockout Gene Expression Profiling Macrophages PTEN Phosphohydrolase Cell Biology medicine.disease Mice Inbred C57BL Systemic inflammatory response syndrome MicroRNAs 030104 developmental biology Cytokine Myeloid Differentiation Factor 88 Cancer research biology.protein Female RNA Interference medicine.symptom Peptides |
| Zdroj: | Sci Signal |
| ISSN: | 1937-9145 1945-0877 |
| DOI: | 10.1126/scisignal.aai9085 |
| Popis: | Sepsis-induced organ damage is caused by systemic inflammatory response syndrome (SIRS), which results in substantial comorbidities. Therefore, it is of medical importance to identify molecular brakes that can be exploited to dampen inflammation and prevent the development of SIRS. We investigated the role of phosphatase and tensin homolog (PTEN) in suppressing SIRS, increasing microbial clearance, and preventing lung damage. Septic patients and mice with sepsis exhibited increased PTEN expression in leukocytes. Myeloid-specific Pten deletion in an animal model of sepsis increased bacterial loads and cytokine production, which depended on enhanced myeloid differentiation primary response gene 88 (MyD88) abundance and resulted in mortality. PTEN-mediated induction of the microRNAs (miRNAs) miR125b and miR203b reduced the abundance of MyD88. Loss- and gain-of-function assays demonstrated that PTEN induced miRNA production by associating with and facilitating the nuclear localization of Drosha-Dgcr8, part of the miRNA-processing complex. Reconstitution of PTEN-deficient mouse embryonic fibroblasts with a mutant form of PTEN that does not localize to the nucleus resulted in retention of Drosha-Dgcr8 in the cytoplasm and impaired production of mature miRNAs. Thus, we identified a regulatory pathway involving nuclear PTEN-mediated miRNA generation that limits the production of MyD88 and thereby limits sepsis-associated mortality. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|