The activation of the inhibitor of NF-κB kinase (IKK) occurs concurrently with the autophagic response. The autophagy essential mediator Beclin 1 binds to both TGFβ-activated kinase 1 binding proteins 2 and 3 (TAB2 and TAB3) which activate the TAK1-IKK signaling axis through their coiled-coil domains. TGF-β activated kinase 1-binding protein 2 (TAB2) and TGF-β activated kinase 1-binding protein 3 (TAB3) separate from Beclin 1 and associate with TAK1 when autophagy is initiated. When TAB2 and TAB3 are overexpressed autophagy gets inhibited but their loss leads to the initiation of autophagy. When TAB2 or TAB3 C-terminal domains combine with Beclin 1's CCD domain expression it interferes with native Beclin 1 binding to TAB2/TAB3 which activates autophagy through a process dependent on endogenous Beclin 1 and TAK1 and IKK.
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Structure and Basic Functions of TAB2 and TAB3
| Project |
TAB2 |
TAB3 |
| Full name |
TAK1 Binding Protein 2 |
TAK1 Binding Protein 3 |
| Main function |
Signal transduction adaptor protein |
Signal transduction adaptor protein |
| Pathway involved |
NF-κB, MAPK, IL-1, TLR signaling |
Highly homologous to TAB2, with similar functions |
| Protein structure |
Contains CUE domain (binds ubiquitin), NZF domain (recognizes polyubiquitin chains) and coiled-coil domain (mediates protein interaction) |
|
TAB2 and TAB3 Involved in Important Physiological Activities
| Physiological processes |
Mechanism of action |
Role of TAB2/3 |
| Maintenance of cell homeostasis |
Maintains autophagy inhibition |
Inhibit Beclin 1 activity |
| Stress response |
Stimulates and induces TAB2/3 dissociation |
Relieve the inhibition of autophagy |
| Immune regulation |
Participates in TLR signaling, autophagy antibacterial response |
Connect NF-κB and autophagy pathways |
| Apoptosis/survival balance |
Cross-regulation of autophagy and apoptosis |
Indirectly affect cell fate determination |
Relationship with TAK1
TAB2 and TAB3 are components of the TAK1 complex and help activate the NF-κB and JNK signaling pathways. The proteins TAB2 and TAB3 function as crucial regulators during inflammation and stress response processes.
Introduction to Beclin 1
Beclin 1 regulates autophagy and manages autophagosome formation at the same time. This protein contained within the Vps34 PI3K complex interacts with multiple proteins to regulate the initiation and progression of autophagy.
Functional Significance
Autophagy Activation
TAB2 and TAB3 interaction activates Beclin 1 resulting in PI3K complex activation that boosts autophagy function during infections and inflammatory stress situations.
Cross-regulation of Inflammation and Autophagy
TAB2/TAB3 links inflammatory signals with the autophagy pathway, allowing cells to coordinate responses to exogenous stimuli.
Disease Relevance
Abnormalities in the TAB2/TAB3–Beclin 1 axis may be associated with cancer, neurodegenerative diseases, infectious diseases, etc.
Interaction of TAB2/TAB3 with Beclin 1
Discovery Background
TAB2 and TAB3 function as TAK1 adaptor proteins within IL-1 and TNF-α inflammatory signal transduction pathways. Recent studies have shown that TAB2/TAB3 can interact with Beclin 1 through its zinc finger (ZF) domain.
Interaction Mechanism
TAB2/TAB3 can recognize and bind to K63-linked ubiquitin chains on Beclin 1. This interaction can recruit Beclin 1 to specific signaling complexes, thereby regulating the activity of autophagy.
TAB2 and TAB3 are endogenous inhibitors of autophagy
Autophagy
Through macroautophagy cells encapsulate parts of the cytoplasm inside autophagosomes which combine with lysosomes to break down their contents. During macroautophagy cytoplasmic components become enclosed within double-membrane autophagosomes through a catabolic process. Autophagosomes transform into autolysosomes through fusion with lysosomes where acid hydrolases break down their contents to release vital nutrients and macromolecules that support cellular metabolism and stress response mechanisms. Beclin 1 serves as an essential component of the autophagy initiation complex (PI3K-III complex) which necessitates exact control over its activity to regulate autophagy.
Mechanism of TAB2/3 Inhibition of Autophagy
The interaction between TAB2 and TAB3 with Beclin 1 becomes possible through their coiled-coil domains. Beclin 1 interaction with TAB2/3 during steady-state conditions deactivates the PI3K-III complex and blocks autophagy initiation. Beclin 1 loses its ability to form a functional complex with the essential autophagy kinase VPS34 when it binds to TAB2/3.
Autophagy induction mechanisms initiated by TAB2 and TAB3 deficiencies or TBD overexpression become ineffective if Beclin 1 or VPS34 are deficient and TAK1 or IKK subunits are inhibited.
References
- Kanayama, A., et al. TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains. Molecular cell. 2004, 15(4): 535-548.
- Criollo, A., et al. Inhibition of autophagy by TAB2 and TAB3. The EMBO journal. 2011, 30(24): 4908-4920.
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