Work

PHLPP1 counter-regulates STAT1-mediated inflammatory signaling

Year: 2019

Type: article

Abstract: ABSTRACT Inflammation is an essential aspect of innate immunity but also contributes to diverse human diseases. Although much is known about the kinases that control inflammatory signaling, less is known about the opposing phosphatases. Here we report that deletion of the gene encoding PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1) protects mice from lethal lipopolysaccharide (LPS) challenge and live Escherichia coli infection. Investigation of PHLPP1 function in macrophages reveals that it controls the magnitude and duration of inflammatory signaling by dephosphorylating the transcription factor STAT1 on Ser727 to inhibit its activity, reduce its promoter residency, and reduce the expression of target genes involved in innate immunity and cytokine signaling. This previously undescribed function of PHLPP1 depends on a bipartite nuclear localization signal in its unique N-terminal extension. Our data support a model in which nuclear PHLPP1 dephosphorylates STAT1 to control the magnitude and duration of inflammatory signaling in macrophages. HIGHLIGHTS PHLPP1 controls the transcription of genes involved in inflammatory signaling PHLPP1 dephosphorylates STAT1 on Ser727 to reduce its transcriptional activity PHLPP1 has a nuclear localization signal and a nuclear exclusion signal Loss of PHLPP1 protects mice from sepsis-induced death

Source: eLife

DOI: 10.7554/elife.48609