Inhibition of Axon Regeneration by Liquid-like TIAR-2 Granules

Neuron. 2019 Oct 23;104(2):290-304.e8. doi: 10.1016/j.neuron.2019.07.004. Epub 2019 Aug 1.


Phase separation into liquid-like compartments is an emerging property of proteins containing prion-like domains (PrLDs), yet the in vivo roles of phase separation remain poorly understood. TIA proteins contain a C-terminal PrLD, and mutations in the PrLD are associated with several diseases. Here, we show that the C. elegans TIAR-2/TIA protein functions cell autonomously to inhibit axon regeneration. TIAR-2 undergoes liquid-liquid phase separation in vitro and forms granules with liquid-like properties in vivo. Axon injury induces a transient increase in TIAR-2 granule number. The PrLD is necessary and sufficient for granule formation and inhibiting regeneration. Tyrosine residues within the PrLD are important for granule formation and inhibition of regeneration. TIAR-2 is also serine phosphorylated in vivo. Non-phosphorylatable TIAR-2 variants do not form granules and are unable to inhibit axon regeneration. Our data demonstrate an in vivo function for phase-separated TIAR-2 and identify features critical for its function in axon regeneration.

Keywords: C. elegans; LLPS; RNA granule; RNA-binding protein; TIA1; axon injury; axon regeneration; liquid-liquid phase separation; prion-like domain; stress granule; tiar-2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Axons / metabolism*
  • Axons / physiology
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Compartmentation
  • Cytoplasmic Granules
  • Nerve Regeneration / physiology*
  • Protein Domains
  • RNA Recognition Motif Proteins / genetics
  • RNA Recognition Motif Proteins / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • T-Cell Intracellular Antigen-1 / genetics
  • T-Cell Intracellular Antigen-1 / metabolism


  • Caenorhabditis elegans Proteins
  • RNA Recognition Motif Proteins
  • RNA-Binding Proteins
  • T-Cell Intracellular Antigen-1
  • TIAR-2 protein, C elegans