Evidence of TRK-Fused Gene (TFG1) function in the ubiquitin-proteasome system

Takuya Yagi, Daisuke Ito, Norihiro Suzuki

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

A heterozygous mutation in the TRK-Fused Gene (TFG1) has recently been identified in hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). TFG1 protein is reportedly localized at endoplasmic reticulum (ER) exit sites and modulates ER export, but the mechanism of its action in neurodegeneration remains unclear. To clarify the molecular pathogenesis of HMSN-P, we examined the biochemical and cellular characteristics of wild-type and mutant (P285L) TFG1 in vitro. A coexpression study of human TFG1 and ER substrates, which are degraded by the ubiquitin-proteasome system (UPS), showed that TFG1 is an inhibitory regulator of the UPS. Deletion mutant constructs revealed that the proline/glutamine-rich domain in TFG1 was critical for regulation of the UPS and proper localization at ER exit sites. Furthermore, overexpression of wild-type TFG1 increased ubiquitination of ER-resident proteins and led to ER stress. Mutant (P285L) TFG1, which is in the proline/glutamine-rich domain, enhanced the inhibitory effect on the UPS and the level of ER stress. These data provide new pathological insights into HMSN-P, and we suspect that the pathogenesis is tightly associated with disruption of intracellular protein homeostasis and ER stress.

Original languageEnglish
Pages (from-to)83-91
Number of pages9
JournalNeurobiology of Disease
Volume66
DOIs
Publication statusPublished - 2014

Fingerprint

Hereditary Sensory and Motor Neuropathy
Proteasome Endopeptidase Complex
Ubiquitin
Endoplasmic Reticulum
Endoplasmic Reticulum Stress
Genes
Glutamine
Proline
Proteins
Ubiquitination
Homeostasis
Mutation

Keywords

  • Amyotrophic lateral sclerosis
  • Endoplasmic reticulum stress
  • Neuropathy
  • TRK-fused gene
  • Ubiquitin-Proteasome system

ASJC Scopus subject areas

  • Neurology

Cite this

Evidence of TRK-Fused Gene (TFG1) function in the ubiquitin-proteasome system. / Yagi, Takuya; Ito, Daisuke; Suzuki, Norihiro.

In: Neurobiology of Disease, Vol. 66, 2014, p. 83-91.

Research output: Contribution to journalArticle

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