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A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals
Cleide G da Silva1, Peter Studer, Marco Skroch
1Division of Vascular and Endovascular Surgery, Center for Vascular Biology Research and the Transplant Institute, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Unlabelled:
Liver regeneration is of major clinical importance in the setting of liver injury, resection, and transplantation. A20, a potent antiinflammatory and nuclear factor kappa B (NF-κB) inhibitory protein, has established pro-proliferative properties in hepatocytes, in part through decreasing expression of the cyclin dependent kinase inhibitor, p21. Both C-terminal (7-zinc fingers; 7Zn) and N-terminal (Nter) domains of A20 were required to decrease p21 and inhibit NF-κB. However, both independently increased hepatocyte proliferation, suggesting that additional mechanisms contributed to the pro-proliferative function of A20 in hepatocytes. We ascribed one of A20's pro-proliferative mechanisms to increased and sustained interleukin (IL)-6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation, as a result of decreased hepatocyte expression of the negative regulator of IL-6 signaling, suppressor of cytokine signaling 3 (SOCS3). This novel A20 function segregates with its 7Zn not Nter domain. Conversely, total and partial loss of A20 in hepatocytes increased SOCS3 expression, hampering IL-6-induced STAT3 phosphorylation. Following liver resection in mice pro-proliferative targets downstream of IL-6/STAT3 signaling were increased by A20 overexpression and decreased by A20 knockdown. In contrast, IL-6/STAT3 proinflammatory targets were increased in A20-deficient livers, and decreased or unchanged in A20 overexpressing livers. Upstream of SOCS3, levels of its microRNA regulator miR203 were significantly decreased in A20-deficient livers.
Conclusion:
A20 enhances IL-6/STAT3 pro-proliferative signals in hepatocytes by down-regulating SOCS3, likely through a miR203-dependent manner. This finding together with A20 reducing the levels of the potent cell cycle brake p21 establishes its pro-proliferative properties in hepatocytes and prompts the pursuit of A20-based therapies to promote liver regeneration and repair.
Insights
A20 protein promotes liver regeneration by enhancing interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling and reducing the cell cycle inhibitor p21. This suggests A20-based therapies could aid liver repair.
Area of Science:
- Hepatology and regenerative medicine
- Molecular biology and cell signaling
- Inflammation and immunology
Background:
- Liver regeneration is crucial for treating liver injury, resection, and transplantation.
- A20 protein exhibits anti-inflammatory and NF-κB inhibitory functions.
- A20 has known pro-proliferative effects on hepatocytes, partly via p21 regulation.
Purpose of the Study:
- To elucidate the mechanisms by which A20 promotes hepatocyte proliferation.
- To investigate the role of A20 in regulating IL-6/STAT3 signaling pathways.
- To determine the functional domains of A20 involved in these processes.
Main Methods:
- Investigated A20's effect on p21 expression and NF-κB activity.
- Assessed A20's impact on IL-6-induced STAT3 phosphorylation via SOCS3 regulation.
- Utilized A20 overexpression and knockdown models in mouse liver resection studies.
- Analyzed microRNA (miR203) regulation of SOCS3.
Main Results:
- A20's C-terminal domain (7Zn) is crucial for decreasing p21 and inhibiting NF-κB.
- A20 enhances sustained IL-6/STAT3 phosphorylation by reducing SOCS3 expression, a mechanism mediated by the 7Zn domain.
- A20 deficiency increases SOCS3, impairing IL-6/STAT3 signaling and potentially involving decreased miR203.
- In vivo, A20 overexpression boosted pro-proliferative IL-6/STAT3 targets post-resection, while knockdown had the opposite effect.
Conclusions:
- A20 promotes hepatocyte proliferation by down-regulating SOCS3, likely via miR203, thereby enhancing IL-6/STAT3 pro-proliferative signals.
- A20's dual action—reducing p21 and boosting IL-6/STAT3 signaling—establishes its pro-proliferative role in hepatocytes.
- These findings support the development of A20-based therapies for promoting liver regeneration and repair.
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