ERK regulates neuroD1-mediated neurite outgrowth via proteasomal degradation

Tae Young Lee, In Su Cho, Narayan Bashyal, Francisco J. Naya, Ming Jer Tsai, Jeong Seon Yoon, Jung Mi Choi, Chang Hwan Park, Sung Soo Kim, Haeyoung Suh-Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Neurogenic differentiation 1 (NeuroD1) is a class B basic helix-loop-helix (bHLH) transcription factor and regulates differentiation and survival of neuronal and endocrine cells by means of several protein kinases, including extracellular signal-regulated kinase (ERK). However, the effect of phosphorylation on the functions of NeuroD1 by ERK has sparked controversy based on context-dependent differences across diverse species and cell types. Here, we evidenced that ERK-dependent phosphorylation controlled the stability of NeuroD1 and consequently, regulated proneural activity in neuronal cells. A null mutation at the ERK-dependent phosphorylation site, S274A, increased the half-life of NeuroD1 by blocking its ubiquitin-dependent proteasomal degradation. The S274A mutation did not interfere with either the nuclear translocation of NeuroD1 or its heterodimerization with E47, its ubiquitous partner and class A bHLH transcription factor. However, the S274A mutant increased transactivation of the E-box-mediated gene and neurite outgrowth in F11 neuroblastoma cells, compared to the wild-type NeuroD1. Transcriptome and Gene Ontology enrichment analyses indicated that genes involved in axonogenesis and dendrite development were downregulated in NeuroD1 knockout (KO) mice. Overexpression of the S274A mutant salvaged neurite outgrowth in NeuroD1-deficient mice, whereas neurite outgrowth was minimal with S274D, a phosphomimicking mutant. Our data indicated that a longer protein half-life enhanced the overall activity of NeuroD1 in stimulating downstream genes and neuronal differentiation. We propose that blocking ubiquitin-dependent proteasomal degradation may serve as a strategy to promote neuronal activity by stimulating the expression of neuron-specific genes in differentiating neurons.

Original languageEnglish
Pages (from-to)189-206
Number of pages18
JournalExperimental Neurobiology
Volume29
Issue number3
DOIs
StatePublished - 2020 Jun 1

Keywords

  • Extracellular signal-regulated kinase
  • Neurite outgrowth
  • Neurogenic differentiation factor 1
  • Phosphorylation

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