Title
Tnfaip8 L1/Oxi-Β Binds To Fbxw5, Increasing Autophagy Through Activation Of Tsc2 In A Parkinson'S Disease Model
Keywords
autophagy; dopamine neuron; mTOR; oxidative stress; Parkinson's disease; TSC2
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. © 2013 International Society for Neurochemistry.
Publication Date
1-1-2014
Publication Title
Journal of Neurochemistry
Volume
129
Issue
3
Number of Pages
527-538
Document Type
Article
Personal Identifier
scopus
DOI Link
https://doi.org/10.1111/jnc.12643
Copyright Status
Unknown
Socpus ID
84899423719 (Scopus)
Source API URL
https://api.elsevier.com/content/abstract/scopus_id/84899423719
STARS Citation
Ha, Ji Young; Kim, Ji Soo; Kang, Young Hee; Bok, Eugene; and Kim, Yoon Seong, "Tnfaip8 L1/Oxi-Β Binds To Fbxw5, Increasing Autophagy Through Activation Of Tsc2 In A Parkinson'S Disease Model" (2014). Scopus Export 2010-2014. 9793.
https://stars.library.ucf.edu/scopus2010/9793