Axonal endoplasmic reticulum tubules control local translation via P180/RRBP1-mediated ribosome interactions

Dev Cell. 2024 Aug 19;59(16):2053-2068.e9. doi: 10.1016/j.devcel.2024.05.005. Epub 2024 May 29.

Abstract

Local mRNA translation in axons is critical for the spatiotemporal regulation of the axonal proteome. A wide variety of mRNAs are localized and translated in axons; however, how protein synthesis is regulated at specific subcellular sites in axons remains unclear. Here, we establish that the axonal endoplasmic reticulum (ER) supports axonal translation in developing rat hippocampal cultured neurons. Axonal ER tubule disruption impairs local translation and ribosome distribution. Using nanoscale resolution imaging, we find that ribosomes make frequent contacts with axonal ER tubules in a translation-dependent manner and are influenced by specific extrinsic cues. We identify P180/RRBP1 as an axonally distributed ribosome receptor that regulates local translation and binds to mRNAs enriched for axonal membrane proteins. Importantly, the impairment of axonal ER-ribosome interactions causes defects in axon morphology. Our results establish a role for the axonal ER in dynamically localizing mRNA translation, which is important for proper neuron development.

Keywords: ER shape; ER-based translation; P180/RRBP1; axonal ER; axonal protein synthesis; endoplasmic reticulum; local translation; mRNA localization; neuron development; ribosomes.

MeSH terms

  • Animals
  • Axons* / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Endoplasmic Reticulum* / metabolism
  • Hippocampus* / metabolism
  • Humans
  • Neurons / metabolism
  • Protein Biosynthesis*
  • RNA, Messenger* / genetics
  • RNA, Messenger* / metabolism
  • Rats
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism
  • Ribosomes* / metabolism

Substances

  • Ribosomal Proteins
  • RNA, Messenger
  • Carrier Proteins