Nuclear PTEN enhances the maturation of a microRNA regulon to limit MyD88-dependent susceptibility to sepsis

Flavia Sisti, Soujuan Wang, Stephanie L. Brandt, Nicole Glosson-Byers, Lindsey Mayo, Young Min Son, Sarah Sturgeon, Luciano Filgueiras, Sonia Jancar, Hector Wong, Charles S.Dela Cruz, Nathaniel Andrews, Jose Carlos Alves-Filho, Fernando Q. Cunha, C. Henrique Serezani

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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 gainof- 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.

Original languageEnglish (US)
Article numbereaai9085
JournalScience Signaling
Volume11
Issue number528
DOIs
StatePublished - May 1 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Sisti, F., Wang, S., Brandt, S. L., Glosson-Byers, N., Mayo, L., Son, Y. M., Sturgeon, S., Filgueiras, L., Jancar, S., Wong, H., Cruz, C. S. D., Andrews, N., Alves-Filho, J. C., Cunha, F. Q., & Serezani, C. H. (2018). Nuclear PTEN enhances the maturation of a microRNA regulon to limit MyD88-dependent susceptibility to sepsis. Science Signaling, 11(528), [eaai9085]. https://doi.org/10.1126/scisignal.aai9085