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

    Authors

    J. Y. Ha; J. S. Kim; Y. H. Kang; E. Bok; Y. S. Kim;J. H. Son

    Comments

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    Abbreviated Journal Title

    J. Neurochem.

    Keywords

    autophagy; dopamine neuron; mTOR; oxidative stress; Parkinson's disease; TSC2; CHAPERONE-MEDIATED AUTOPHAGY; NEUROBLASTOMA SH-SY5Y CELLS; TUBEROUS; SCLEROSIS; ALPHA-SYNUCLEIN; SUBSTANTIA-NIGRA; OXIDATIVE STRESS; IN-VIVO; DEATH; PROTEIN; NEURONS; Biochemistry & Molecular Biology; Neurosciences

    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-alpha, 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 Tnfaip8l1/Oxi-beta could increase autophagy by a unique mechanism that increases the stability of tuberous sclerosis complex 2 (TSC2), a critical negative regulator of mTOR. Tnfaip8l1/Oxi-beta and Tnfaip8/Oxi-alpha are the novel regulators of mTOR acting in opposition in dopaminergic (DA) neurons. Specifically, 6-hydroxydopamine (6-OHDA) treatment up-regulated Tnfaip8l1/Oxi-beta in DA neurons, thus inducing autophagy, while knockdown of Tnfaip8l1/Oxi-beta prevented significantly activation of autophagic markers by 6-OHDA. FBXW5 was identified as a novel binding protein for Tnfaip8l1/Oxi-beta. FBXW5 is a TSC2 binding receptor within CUL4 E3 ligase complex, and it promotes proteasomal degradation of TSC2. Thus, Tnfaip8l1/Oxi-beta competes with TSC2 to bind FBXW5, increasing TSC2 stability by preventing its ubiquitination. Our data show that the OS-induced Tnfaip8l1/Oxi-beta stabilizes TSC2 protein, decreases mTOR phosphorylation, and enhances autophagy. Therefore, altered regulation of Tnfaip8l1/Oxi-beta may contribute significantly to dysregulated autophagy observed in dopaminergic neurons under pathogenic OS condition.

    Journal Title

    Journal of Neurochemistry

    Volume

    129

    Issue/Number

    3

    Publication Date

    1-1-2014

    Document Type

    Article

    Language

    English

    First Page

    527

    Last Page

    538

    WOS Identifier

    WOS:000334489100016

    ISSN

    0022-3042

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