DAF-16/FOXO requires Protein Phosphatase 4 to initiate transcription of stress resistance and longevity promoting genes

Ilke Sen, Xin Zhou, Alexey Chernobrovkin, Nataly Puerta-Cavanzo, Takaharu Kanno, Jerome Salignon, Andrea Stoehr, Xin-Xuan Lin, Bora Baskaner, Simone Brandenburg, Camilla Bjorkegren, Roman A. Zubarev, Christian G. Riedel*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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Abstract

In C. elegans, the conserved transcription factor DAF-16/FOXO is a powerful aging regulator, relaying dire conditions into expression of stress resistance and longevity promoting genes. For some of these functions, including low insulin/IGF signaling (IIS), DAF-16 depends on the protein SMK-1/SMEK, but how SMK-1 exerts this role has remained unknown. We show that SMK-1 functions as part of a specific Protein Phosphatase 4 complex (PP4(SMK-1)). Loss of PP4(SMK-1) hinders transcriptional initiation at several DAF-16-activated genes, predominantly by impairing RNA polymerase II recruitment to their promoters. Search for the relevant substrate of PP4(SMK-1) by phosphoproteomics identified the conserved transcriptional regulator SPT-5/SUPT5H, whose knockdown phenocopies the loss of PP4(SMK-1). Phosphoregulation of SPT-5 is known to control transcriptional events such as elongation and termination. Here we also show that transcription initiating events are influenced by the phosphorylation status of SPT-5, particularly at DAF-16 target genes where transcriptional initiation appears rate limiting, rendering PP4(SMK-1) crucial for many of DAF-16's physiological roles.

Original languageEnglish
Article number138
Number of pages17
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 9-Jan-2020

Keywords

  • ELEGANS LIFE-SPAN
  • COMPLEX
  • DNA
  • GROWTH
  • SPT5
  • PHOSPHORYLATION
  • ACTIVATION
  • REGULATOR
  • MUTANT
  • DOMAIN

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