Evolutionarily conserved regulation of immunity by the splicing factor RNP-6/PUF60

Elife. 2020 Jun 15;9:e57591. doi: 10.7554/eLife.57591.

Abstract

Splicing is a vital cellular process that modulates important aspects of animal physiology, yet roles in regulating innate immunity are relatively unexplored. From genetic screens in C. elegans, we identified splicing factor RNP-6/PUF60 whose activity suppresses immunity, but promotes longevity, suggesting a tradeoff between these processes. Bacterial pathogen exposure affects gene expression and splicing in a rnp-6 dependent manner, and rnp-6 gain and loss-of-function activities reveal an active role in immune regulation. Another longevity promoting splicing factor, SFA-1, similarly exerts an immuno-suppressive effect, working downstream or parallel to RNP-6. RNP-6 acts through TIR-1/PMK-1/MAPK signaling to modulate immunity. The mammalian homolog, PUF60, also displays anti-inflammatory properties, and its levels swiftly decrease after bacterial infection in mammalian cells, implying a role in the host response. Altogether our findings demonstrate an evolutionarily conserved modulation of immunity by specific components of the splicing machinery.

Keywords: C. elegans; ageing; genetics; genomics; immunology; inflammation; innate immunity; splicing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Anti-Inflammatory Agents
  • Bacterial Infections / metabolism
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans / microbiology
  • Caenorhabditis elegans Proteins / metabolism
  • DNA-Binding Proteins / metabolism
  • Escherichia coli
  • Gene Expression
  • HeLa Cells
  • Humans
  • Immunity, Innate*
  • Longevity / genetics
  • Male
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • RAW 264.7 Cells
  • RNA Splicing Factors / metabolism*
  • RNA, Messenger / metabolism
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Staphylococcus aureus

Substances

  • Anti-Inflammatory Agents
  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • RNA Splicing Factors
  • RNA, Messenger
  • Repressor Proteins
  • poly-U binding splicing factor 60KDa
  • rnp-6 protein, C elegans
  • sfa-1 protein, C elegans
  • Mitogen-Activated Protein Kinases
  • Pmk-1 protein, C elegans

Associated data

  • GEO/GSE141097

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.