RRC ID 59590
Author Sen I, Zhou X, Chernobrovkin A, Puerta-Cavanzo N, Kanno T, Salignon J, Stoehr A, Lin XX, Baskaner B, Brandenburg S, Björkegren C, Zubarev RA, Riedel CG.
Title DAF-16/FOXO requires Protein Phosphatase 4 to initiate transcription of stress resistance and longevity promoting genes.
Journal Nat Commun
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.
Volume 11(1)
Pages 138
Published 2020-1-9
DOI 10.1038/s41467-019-13931-7
PII 10.1038/s41467-019-13931-7
PMID 31919361
PMC PMC6952425
MeSH 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*
IF 11.878
Times Cited 0
C.elegans tm2993 tm1445