Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-�-induced Neuronal Death
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Tribbles Pseudokinase 3 Induces Both Apoptosis and
Autophagy in Amyloid-�-induced Neuronal Death
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| Creator |
Saleem, Suraiya
Biswas, Subhas Chandra |
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| Subject |
Cell Biology & Physiology
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| Description |
Amyloid-� (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. Wefound 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.
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| Publisher |
American Society for Biochemistry and Molecular Biology
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| Date |
2017-02-17
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2655/1/THE_JOURNAL_OF_BIOLOGICAL_CHEMISTRY_VOL._292%2C_NO._7.pdf
Saleem, Suraiya and Biswas, Subhas Chandra (2017) Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-�-induced Neuronal Death. The Journal of Biological Chemistry, 279 (7). pp. 2571-2585. |
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| Relation |
http://www.eprints.iicb.res.in/2655/
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