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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

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Sisti, Flavia [1] ; Wang, Soujuan [1] ; Brandt, Stephanie L. [1, 2] ; Glosson-Byers, Nicole [1] ; Mayo, Lindsey D. [3, 4] ; Son, Young Min [1] ; Sturgeon, Sarah [2] ; Filgueiras, Luciano [5, 1] ; Jancar, Sonia [5] ; Wong, Hector [6, 7] ; Dela Cruz, Charles S. [8] ; Andrews, Nathaniel [8] ; Alves-Filho, Jose Carlos [9] ; Cunha, Fernando Q. [9] ; Serezani, C. Henrique [1, 2]
Número total de Autores: 15
Afiliação do(s) autor(es):
[1] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 - USA
[2] Vanderbilt Univ, Med Ctr, Dept Med, Div Infect Dis, 221 Kirkland Hall, Nashville, TN 37235 - USA
[3] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Dept Pediat, Indianapolis, IN 46202 - USA
[4] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Dept Biochem & Mol Biol, Indianapolis, IN 46202 - USA
[5] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, BR-05508000 Sao Paulo - Brazil
[6] Cincinnati Childrens Hosp Med Ctr, Div Crit Care Med, Cincinnati, OH 45229 - USA
[7] Cincinnati Childrens Hosp Res Fdn, Cincinnati, OH 45229 - USA
[8] Yale Univ, Sch Med, Dept Internal Med, Sect Pulm & Critical Care Med, New Haven, CT 06520 - USA
[9] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, BR-14049900 Ribeirao Preto - Brazil
Número total de Afiliações: 9
Tipo de documento: Artigo Científico
Fonte: Science Signaling; v. 11, n. 528 MAY 1 2018.
Citações Web of Science: 1

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. (AU)

Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
Beneficiário:Fernando de Queiroz Cunha
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 11/19670-0 - Mecanismos envolvidos na fisiopatologia da artrite reumatóide, dor e sepse
Beneficiário:Fernando de Queiroz Cunha
Linha de fomento: Auxílio à Pesquisa - Temático