TDP2 negatively regulates axon regeneration by inducing SUMOylation of an Ets transcription factor

EMBO Rep. 2019 Oct 4;20(10):e47517. doi: 10.15252/embr.201847517. Epub 2019 Aug 8.

Abstract

In Caenorhabditis elegans, the JNK MAP kinase (MAPK) pathway is important for axon regeneration. The JNK pathway is activated by a signaling cascade consisting of the growth factor SVH-1 and its receptor tyrosine kinase SVH-2. Expression of the svh-2 gene is induced by axonal injury in a process involving the transcription factors ETS-4 and CEBP-1. Here, we find that svh-14/mxl-1, a gene encoding a Max-like transcription factor, is required for activation of svh-2 expression in response to axonal injury. We show that MXL-1 binds to and inhibits the function of TDPT-1, a C. elegans homolog of mammalian tyrosyl-DNA phosphodiesterase 2 [TDP2; also called Ets1-associated protein II (EAPII)]. Deletion of tdpt-1 suppresses the mxl-1 defect, but not the ets-4 defect, in axon regeneration. TDPT-1 induces SUMOylation of ETS-4, which inhibits ETS-4 transcriptional activity, and MXL-1 counteracts this effect. Thus, TDPT-1 interacts with two different transcription factors in axon regeneration.

Keywords: C. elegans; Ets; SUMOylation; TDP2/EAPII; axon regeneration.

Publication types

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

MeSH terms

  • Animals
  • Axons / physiology*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / metabolism*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation
  • Models, Biological
  • Motor Neurons / metabolism
  • Nerve Regeneration*
  • Phosphoric Diester Hydrolases / metabolism*
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins c-ets / metabolism*
  • Sumoylation*
  • Transcription Factors / metabolism*
  • Transcription, Genetic

Substances

  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • ETS-4 protein, C elegans
  • MXL-1 protein, C elegans
  • Proto-Oncogene Proteins c-ets
  • Transcription Factors
  • Phosphoric Diester Hydrolases
  • tdpt-1 protein, C elegans