Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-β-induced Neuronal Death

Abstract

Edited by Paul E. FraserAmyloid-␤ (A␤)-induced neuron death is considered central to the pathogenesis of Alzheimer's disease (AD). Among several death modalities, autophagy and apoptosis play important roles in A␤-induced neuron death suggesting that there may be regulatory mechanisms that initiate both cell death pathways. However, molecules that govern both pathways have not been identified. Here, we report that, upon A␤ treatment, tribbles pseudokinase 3 (Trib3, an ortholog of Drosophila Tribbles) is up-regulated in neurons both in vivo and in vitro. Increased Trib3 levels inhibited the activity of the kinase Akt by interacting with it. As a result, forkhead box O1 (FoxO1), a transcription factor that is negatively regulated by Akt, was activated, translocated to the nucleus, and induced the pro-apoptotic gene BCL2-like 11 (Bim). Conversely, FoxO1 responded to A␤ insult by binding to the Trib3 gene promoter, enhancing its expression. Our investigations further revealed that Trib3 also induces autophagy. We found that Trib3 indirectly activates unc-51-like autophagy-activating kinase1 (Ulk1) by impeding phosphorylation of, and thus inactivating, a negative regulator of Ulk1, mechanistic target of rapamycin. Ulk1 activation augmented autophagosome formation and reduced autophagy flux. Thus, Trib3 was required for formation of autophagosomes, which accumulated in neurons as autophagic flux was thwarted. Most importantly, silencing endogenous Trib3 strongly protected neurons from A␤ insult. Our results suggest that a self-amplifying feed-forward loop among Trib3, Akt, and FoxO1 in A␤-treated neurons induces both apoptosis and autophagy, culminating in neuron death. Thus, Trib3 may serve as a potential therapeutic target for AD.

Apoptotic cell death regulation in neurons

“…However, Puma is frequently co‐upregulated with Bim and their promoters have in common binding sites for several transcription factors including c‐Jun , FoxO3a and CHOP . The FoxO transcription factors FoxO1 and FoxO3a are activated downstream of AMPK , Trib3 , MST1 or Cdk5/p35 in response to stimuli such as NGF withdrawal, oxidative stress or amyloid β to mediate Bim induction. Typically, these kinases facilitate FoxO nuclear translocation by relieving either Akt‐ or 14‐3‐3‐mediated inhibition or sequestration of FoxO transcription factors.…”

“…Additionally, neuronal Akt restricts the BH3-only protein Bad through a mechanism involving direct phosphorylation of Bad that reduces Bad binding to Bcl-xL and increases Bad interaction and sequestration by the 14-3-3 proteins [32,[57][58][59]. Active suppression of Akt prosurvival signaling, which occurs via its direct phosphorylation and inactivation by AMPK and Trib3, is required for the apoptosis to proceed in response to neurotoxic stimuli [65][66][67][68].…”

“…Broadly speaking, the survival pathways that repress the expression of BH3-only proteins in healthy neurons are the PI3K/Akt and the MEK/ERK pathways. For example, neuronal Akt and ERK5 repress FoxO3a transcription factor and suppression of Akt or ERK5 is sufficient to promote Bim expression [56,[65][66][67][68]158]. The pro-survival MEK-ERK signaling pathway can also promote the proteasomal degradation of Bim [159][160][161][162].…”

Forkhead Transcription Factors: Formulating a FOXO Target for Cognitive Loss

“…Blockade of FoxO activity can protect against oxidative stress and Aβ toxicity (58, 94). Increased FoxO activity can function in concert with tribbles pseudokinase 3 to result in apoptotic and autophagic Aβ induced neuronal cell death (95). …”

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

“…Under some conditions, Aβ exposure can result in the dephosphorylation and mitochondrial translocation of FoxO3a that leads to mitochondrial dysfunction (196). Furthermore, increased FoxO activity can function in concert with tribbles pseudokinase 3 to result in apoptotic and autophagic Aβ induced neuronal cell death (79). Inhibition of FoxO activity under such conditions can protect against oxidative stress and Aβ toxicity (208, 229).…”