Tnfaip8 l1/Oxi-β binds to FBXW5, increasing autophagy through activation of TSC2 in a Parkinson's disease model

Ji Young Ha, Ji Soo Kim, Young Hee Kang, Eugene Bok, Yoon Seong Kim, Jin H. Son

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Abnormal autophagy may contribute to neurodegeneration in Parkinson's disease (PD). However, it is largely unknown how autophagy is dysregulated by oxidative stress (OS), one of major pathogenic causes of PD. We recently discovered the potential autophagy regulator gene family including Tnfaip8/Oxi-α, which is a mammalian target of rapamycin (mTOR) activator down-regulated by OS in dopaminergic neurons (J. Neurochem., 112, 2010, 366). Here, we demonstrate that the OS-induced Tnfaip8 l1/Oxi-β could increase autophagy by a unique mechanism that increases the stability of tuberous sclerosis complex 2 (TSC2), a critical negative regulator of mTOR. Tnfaip8 l1/Oxi-β and Tnfaip8/Oxi-α are the novel regulators of mTOR acting in opposition in dopaminergic (DA) neurons. Specifically, 6-hydroxydopamine (6-OHDA) treatment up-regulated Tnfaip8 l1/Oxi-β in DA neurons, thus inducing autophagy, while knockdown of Tnfaip8 l1/Oxi-β prevented significantly activation of autophagic markers by 6-OHDA. FBXW5 was identified as a novel binding protein for Tnfaip8 l1/Oxi-β. FBXW5 is a TSC2 binding receptor within CUL4 E3 ligase complex, and it promotes proteasomal degradation of TSC2. Thus, Tnfaip8 l1/Oxi-β competes with TSC2 to bind FBXW5, increasing TSC2 stability by preventing its ubiquitination. Our data show that the OS-induced Tnfaip8 l1/Oxi-β stabilizes TSC2 protein, decreases mTOR phosphorylation, and enhances autophagy. Therefore, altered regulation of Tnfaip8 l1/Oxi-β may contribute significantly to dysregulated autophagy observed in dopaminergic neurons under pathogenic OS condition.

Original languageEnglish (US)
Pages (from-to)527-538
Number of pages12
JournalJournal of neurochemistry
Volume129
Issue number3
DOIs
StatePublished - May 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

Keywords

  • Parkinson's disease
  • TSC2
  • autophagy
  • dopamine neuron
  • mTOR
  • oxidative stress

Fingerprint

Dive into the research topics of 'Tnfaip8 l1/Oxi-β binds to FBXW5, increasing autophagy through activation of TSC2 in a Parkinson's disease model'. Together they form a unique fingerprint.

Cite this