RTN3 Is a Novel Cold-Induced Protein and Mediates Neuroprotective Effects of RBM3

Curr Biol. 2017 Mar 6;27(5):638-650. doi: 10.1016/j.cub.2017.01.047. Epub 2017 Feb 23.


Cooling and hypothermia are profoundly neuroprotective, mediated, at least in part, by the cold shock protein, RBM3. However, the neuroprotective effector proteins induced by RBM3 and the mechanisms by which mRNAs encoding cold shock proteins escape cooling-induced translational repression are unknown. Here, we show that cooling induces reprogramming of the translatome, including the upregulation of a new cold shock protein, RTN3, a reticulon protein implicated in synapse formation. We report that this has two mechanistic components. Thus, RTN3 both evades cooling-induced translational elongation repression and is also bound by RBM3, which drives the increased expression of RTN3. In mice, knockdown of RTN3 expression eliminated cooling-induced neuroprotection. However, lentivirally mediated RTN3 overexpression prevented synaptic loss and cognitive deficits in a mouse model of neurodegeneration, downstream and independently of RBM3. We conclude that RTN3 expression is a mediator of RBM3-induced neuroprotection, controlled by novel mechanisms of escape from translational inhibition on cooling.

Keywords: RBM3; RTN3; cold shock; mRNA translation; neuroprotection; protein synthesis.

MeSH terms

  • Animals
  • Cold Shock Proteins and Peptides / genetics*
  • Cold Shock Proteins and Peptides / metabolism
  • Cold Temperature
  • Cold-Shock Response / genetics*
  • HEK293 Cells
  • Humans
  • Mice
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neuroprotective Agents / metabolism
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism


  • Cold Shock Proteins and Peptides
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • RNA-Binding Proteins
  • Rbm3 protein, mouse
  • Rtn3 protein, mouse