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

Nat Commun. 2020 Jan 9;11(1):138. doi: 10.1038/s41467-019-13931-7.

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 (PP4SMK-1). Loss of PP4SMK-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 PP4SMK-1 by phosphoproteomics identified the conserved transcriptional regulator SPT-5/SUPT5H, whose knockdown phenocopies the loss of PP4SMK-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 PP4SMK-1 crucial for many of DAF-16's physiological roles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics*
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Forkhead Transcription Factors / genetics*
  • Gene Expression Regulation / genetics*
  • Longevity / genetics
  • Multiprotein Complexes / metabolism
  • Phosphoprotein Phosphatases / genetics*
  • Phosphoprotein Phosphatases / metabolism*
  • RNA Interference
  • RNA Polymerase II / metabolism
  • Stress, Physiological / genetics
  • Transcription, Genetic / genetics
  • Transcriptional Elongation Factors / genetics
  • Transcriptional Elongation Factors / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Chromosomal Proteins, Non-Histone
  • Forkhead Transcription Factors
  • Multiprotein Complexes
  • Transcriptional Elongation Factors
  • daf-16 protein, C elegans
  • SPT5 transcriptional elongation factor
  • RNA Polymerase II
  • Phosphoprotein Phosphatases
  • SMK-1 protein, C elegans
  • protein phosphatase 4