Phosphatidylcholine mediates the crosstalk between LET-607 and DAF-16 stress response pathways

PLoS Genet. 2021 May 20;17(5):e1009573. doi: 10.1371/journal.pgen.1009573. eCollection 2021 May.

Abstract

Coordinated regulation of stress response pathways is crucial for cellular homeostasis. However, crosstalk between the different stress pathways and the physiological significance of this crosstalk remain poorly understood. In this study, using the model organism C. elegans, we discovered that suppression of the transcription factor LET-607/CREBH, a regulator of cellular defense and proteostatic responses, triggers adaptive induction of DAF-16-dependent stress responses. Suppression of LET-607 improves stress resistance and extends C. elegans lifespan in a DAF-16-dependent manner. We identified the sphingomyelin synthase SMS-5 to be a central mediator in the communication between LET-607 and DAF-16. SMS-5 reduces the contents of unsaturated phosphatidylcholine (PC), which activates DAF-16 through ITR-1-dependent calcium signaling and calcium-sensitive kinase PKC-2. Our data reveal the significance of crosstalk between different stress pathways in animal fitness and identify LET-607/CREBH and specific PC as regulators of DAF-16 and longevity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / metabolism*
  • Calcium Signaling
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Forkhead Transcription Factors / metabolism*
  • Germ-Line Mutation
  • Longevity / genetics
  • Membrane Lipids / metabolism
  • Nerve Tissue Proteins / metabolism*
  • Phosphatidylcholines / metabolism*
  • Protein Kinase C / metabolism
  • Stress, Physiological*
  • Transferases (Other Substituted Phosphate Groups) / genetics
  • Transferases (Other Substituted Phosphate Groups) / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Forkhead Transcription Factors
  • Membrane Lipids
  • Nerve Tissue Proteins
  • Phosphatidylcholines
  • daf-16 protein, C elegans
  • PKC-2 protein, C elegans
  • Protein Kinase C
  • Transferases (Other Substituted Phosphate Groups)
  • phosphatidylcholine-ceramide phosphocholine transferase
  • sms-5 protein, C elegans

Grants and funding

This work was supported by National Natural Science Foundation of China (grant No. 32070754, 31701017 to H.T. and grant No. 31771337, 32071163 to S. P.), Natural Science Foundation of Chongqing, China (grant No. cstc2020jcyj-msxmX0714 to H.T.) and Chongqing Talents Plan for Young Talents (CQYC201905071 to S.P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.