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, Jérôme Salignon, Andrea Stoehr, Xin-Xuan Lin, Bora Baskaner, Simone Brandenburg, Camilla Björkegren, Roman A. Zubarev and Christian G. Riedel ()
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Ilke Sen: Karolinska Institute
Xin Zhou: Karolinska Institute
Alexey Chernobrovkin: Karolinska Institute
Nataly Puerta-Cavanzo: University Medical Center Groningen (UMCG), University of Groningen
Takaharu Kanno: Karolinska Institute
Jérôme Salignon: Karolinska Institute
Andrea Stoehr: Karolinska Institute
Xin-Xuan Lin: Karolinska Institute
Bora Baskaner: Karolinska Institute
Simone Brandenburg: University Medical Center Groningen (UMCG), University of Groningen
Camilla Björkegren: Karolinska Institute
Roman A. Zubarev: Karolinska Institute
Christian G. Riedel: Karolinska Institute

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13931-7

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