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The tumor suppressor phosphatase PHLPP1 suppresses inflammatory signaling by regulating the phosphorylation state and activity of STAT1
Author(s) -
Katsenelson Ksenya Cohen,
Stender Joshua D.,
Uchiyama Satoshi,
Nizet Victor,
Glass Chris K.,
Newton Alexandra C.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.648.11
Subject(s) - stat1 , phosphorylation , dephosphorylation , transcription factor , biology , protein phosphatase 1 , phosphatase , promoter , transcriptional regulation , signal transduction , gene , gene expression , microbiology and biotechnology , chemistry , biochemistry
Post‐translational modifications, such as phosphorylation, play a key role in regulating gene expression. Although much is known about the kinases that control epigenetic mechanisms, much less is known about the phosphatases. Here we report that the PH domain Leucine Rich Repeat Protein Phosphatase 1 (PHLPP1) regulates the transcription of a large number of genes by a mechanism that depends, in part, on the dephosphorylation of the transcription factor STAT1. Using non‐biased high‐throughput RNA‐sequencing, we analyzed genome‐wide mRNA levels of genes in lipopolysaccharide (LPS)‐treated bone marrow‐derived macrophages from wild‐type and Phlpp1−/− mice and found that approximately 1600 transcripts were up or down‐regulated 2‐fold or more in the Phlpp1−/− macrophages. Gene ontology analysis revealed that many of the genes that were upregulated upon loss of PHLPP1 are involved in proinflammatory signaling. De novo motif analysis of the promoters for those genes revealed that 46% of them have recognition motifs for STAT1, a key regulatory transcription factor of inflammatory signaling. Biochemical analysis revealed that PHLPP1 regulates the phosphorylation of STAT1 on Ser727, a site that is important for full transcriptional activity of STAT1, but not Tyr701, a site that recruits STAT1 to the nucleus. Importantly, PHLPP1 deletion resulted in enhanced downstream inflammatory signaling as assessed by a luciferase reporter assay of the Interferon‐Gamma Activated Sequence (GAS) promoter. In addition to the new finding that PHLPP1 is controlling inflammatory signaling, Phlpp1−/− mice are protected from sepsis‐induced death. Our data support a model in which PHLPP1 plays a previously undescribed role in regulating inflammation which has potential therapeutic implications for sepsis‐induced death. Support or Funding Information NIH/NCI T32 CA009523 (K.C.K.) NIH Grant R01 GM067946 (A.C.N.) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .