HuD Is a Neural Translation Enhancer Acting on mTORC1-Responsive Genes and Counteracted by the Y3 Small Non-coding RNA

Mol Cell. 2018 Jul 19;71(2):256-270.e10. doi: 10.1016/j.molcel.2018.06.032.

Abstract

The RNA-binding protein HuD promotes neurogenesis and favors recovery from peripheral axon injury. HuD interacts with many mRNAs, altering both stability and translation efficiency. We generated a nucleotide resolution map of the HuD RNA interactome in motor neuron-like cells, identifying HuD target sites in 1,304 mRNAs, almost exclusively in the 3' UTR. HuD binds many mRNAs encoding mTORC1-responsive ribosomal proteins and translation factors. Altered HuD expression correlates with the translation efficiency of these mRNAs and overall protein synthesis, in a mTORC1-independent fashion. The predominant HuD target is the abundant, small non-coding RNA Y3, amounting to 70% of the HuD interaction signal. Y3 functions as a molecular sponge for HuD, dynamically limiting its recruitment to polysomes and its activity as a translation and neuron differentiation enhancer. These findings uncover an alternative route to the mTORC1 pathway for translational control in motor neurons that is tunable by a small non-coding RNA.

Keywords: HuD ELAVL4; NSC-34; RNA binding protein; Y RNA; Y3 Rny3; mTORC1; neuron differentiation; non-coding RNA; polysomes; translation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • ATP Binding Cassette Transporter, Subfamily B, Member 2
  • Animals
  • Cell Line
  • ELAV-Like Protein 4 / genetics*
  • ELAV-Like Protein 4 / metabolism
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / genetics*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Motor Neurons / metabolism
  • Motor Neurons / physiology*
  • Neurogenesis / genetics
  • Polyribosomes / metabolism
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Untranslated / genetics*
  • RNA, Small Untranslated / metabolism

Substances

  • 3' Untranslated Regions
  • ATP Binding Cassette Transporter, Subfamily B, Member 2
  • ELAV-Like Protein 4
  • ELAVL4 protein, human
  • Elavl4 protein, mouse
  • RNA, Long Noncoding
  • RNA, Messenger
  • RNA, Small Untranslated
  • Tap1 protein, mouse
  • Y3 non-coding RNA, human
  • Mechanistic Target of Rapamycin Complex 1