TRIB3‒GSK-3β interaction promotes lung fibrosis and serves as a potential therapeutic target.
TRIB3‒GSK-3β interaction promotes lung fibrosis and serves as a potential therapeutic target.
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TRIB3-GSK-3β 相互作用促进肺纤维化并作为潜在的治疗靶点
DOI：
10.1016/j.apsb.2021.06.017
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Cui B
中科院分区：
文献类型：
--
作者：
Liu S;Lv X;Wei X;Liu C;Li Q;Min J;Hua F;Zhang X;Li K;Li P;Xiao Y;Hu Z;Cui B
肺纤维化（PF）是一种慢性、进行性、致死性间质性肺疾病，目前可用的治疗策略有限。我们最近报道了蛋白激酶糖原合成酶激酶-3 β（GSK-3β）与泛素编辑酶A20相互作用并使其失活，以抑制肺泡巨噬细胞（AM）中转录因子CCAAT/增强子结合蛋白β（C/EBPβ）的降解，导致AM的促纤维化表型并促进PF的发展。我们发现，慢性肺损伤上调应激反应蛋白tribbles同系物3（TRIB 3），TRIB 3与GSK-3β相互作用，稳定GSK-3β的泛素化和降解。GSK-3β表达升高会磷酸化A20以抑制其遍在蛋白编辑活性，导致AM中C/EBPβ的积累和几种促纤维化因子的产生，并促进PF的发展。激活的C/EBPβ反过来又增加TRIB 3和GSK-3β的转录，从而在AM中建立正反馈回路。TRIB 3表达的敲低或TRIB 3与GSK-3β相互作用的药理学破坏是有效的PF治疗。我们的研究揭示了AM中TRIB 3-GSK-3β-A20-C/EBPβ的完整促纤维化轴，这代表了可能为PF提供有希望的治疗策略的靶点。巨噬细胞中TRIB 3表达升高与肺纤维化的发展呈正相关。TRIB 3与GSK-3β的相互作用阻碍GSK-3β的泛素化和降解。靶向TRIB 3与GSK-3β相互作用可减少肺纤维化。
Pulmonary fibrosis (PF) is a chronic, progressive, fatal interstitial lung disease with limited available therapeutic strategies. We recently reported that the protein kinase glycogen synthase kinase-3β (GSK-3β) interacts with and inactivates the ubiquitin-editing enzyme A20 to suppress the degradation of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ) in alveolar macrophages (AMs), resulting in a profibrotic phenotype of AMs and promoting the development of PF. Here, we showed that chronic lung injury upregulated the stress response protein tribbles homolog 3 (TRIB3), which interacted with GSK-3β and stabilized GSK-3β from ubiquitination and degradation. Elevated GSK-3β expression phosphorylated A20 to inhibit its ubiquitin-editing activity, causing the accumulation of C/EBPβ and the production of several profibrotic factors in AMs and promoting PF development. Activated C/EBPβ, in turn, increased the transcription of TRIB3 and GSK-3β, thereby establishing a positive feedback loop in AMs. The knockdown of TRIB3 expression or the pharmacologic disruption of the TRIB3‒GSK-3β interaction was an effective PF treatment. Our study reveals an intact profibrotic axis of TRIB3‒GSK-3β‒A20‒C/EBPβ in AMs, which represents a target that may provide a promising treatment strategy for PF. Elevated TRIB3 expression in macrophages positively correlates with the development of pulmonary fibrosis. TRIB3 interaction with GSK-3β obstructs the ubiquitination and degradation of GSK-3β. Targeting TRIB3‒GSK-3β interaction reduces pulmonary fibrosis.
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影响因子：
7.4
作者：
Osborn-Heaford HL;Murthy S;Gu L;Larson-Casey JL;Ryan AJ;Shi L;Glogauer M;Neighbors JD;Hohl R;Carter AB
通讯作者：
Carter AB
影响因子：
7.3
作者：
Kilkenny, Carol;Browne, William;Altman, Douglas G.
通讯作者：
Altman, Douglas G.
影响因子：
4.8
作者：
He, Chao;Ryan, Alan J.;Carter, A. Brent
通讯作者：
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影响因子：
32.4
作者：
Larson-Casey JL;Deshane JS;Ryan AJ;Thannickal VJ;Carter AB
通讯作者：
Carter AB
卢帕他定通过减轻 PAF 介导的啮齿动物衰老来预防肺纤维化
影响因子：
3.7
作者：
Lv XX;Wang XX;Li K;Wang ZY;Li Z;Lv Q;Fu XM;Hu ZW
通讯作者：
Hu ZW