TRIB3‒GSK-3β interaction promotes lung fibrosis and serves as a potential therapeutic target

Abstract

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-3 β (GSK-3 β ) interacts with and inactivates the ubiquitin-editing enzyme A20 to suppress the degradation of the transcription factor CCAAT/enhancer-binding protein beta (C/EBP β ) 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-3 β and stabilized GSK-3 β from ubiquitination and degradation. Elevated GSK-3 β expression phosphorylated A20 to inhibit its ubiquitin-editing activity, causing the accumulation of C/EBP β and the production of several profibrotic factors in AMs and promoting PF development. Activated C/EBP β , in turn, increased the transcription of TRIB3 and GSK-3 β , thereby establishing a positive feedback loop in AMs. The knockdown of TRIB3 expression or the pharmacologic disruption of the TRIB3‒GSK-3 β interaction was an effective PF treatment. Our study reveals an intact profibrotic axis of TRIB3‒GSK-3 β ‒A20‒C/EBP β in AMs, which represents a target that may provide a promising treatment strategy for PF.

TRAF6 Suppresses the Development of Pulmonary Fibrosis by Attenuating the Activation of Fibroblasts

“…Accumulating evidence has widely demonstrated that TRIB3 plays a vital role in organ fibrogenesis ( Wang et al, 2014 ; Tomcik et al, 2016 ; Zhang et al, 2020 ). Our previous study, along with others, reported the key role of TRIB3 in promoting PF ( Yu W. et al, 2019 ; Liu S. et al, 2021 ). We found that TRIB3 was substantially upregulated in alveolar macrophages (AMs) from patients with PF, inducing the profibrotic phenotype of AMs.…”

“…These data indicated that the decreased protein expression of TRAF6 in lung fibroblasts during PF progression might result from an alteration in its protein stability. Our group, along with others, has reported that TRIB3, a well-known stress sensor, is involved in regulating the stability of various proteins in the pathogenesis of chronic diseases ( Lin et al, 2019 ; Yu J. M. et al, 2019 ; Liu S. et al, 2021 ). We then reasoned that TRIB3 might participate in regulating the altered protein expression of TRAF6.…”

“…As a member of the pseudokinase family, TRIB3 was found to regulate diverse processes in the progression of various diseases by interacting with functional proteins. For instance, the interaction of TRIB3 and the protein kinase GSK-3β interferes with the binding of GSK-3β to the E3 ligase UHRF1, thereby inhibiting the degradation of GSK-3β and leading to the profibrotic phenotype of Ams ( Liu S. et al, 2021 ). TRIB3 interacted with MYC to suppress E3 ubiquitin ligase UBE3B-mediated MYC degradation, which induced the enhanced expression of MYC, causing the proliferation of lymphoma cells ( Li K. et al, 2020 ).…”

CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding

“…Recent studies have shown that C/EBP β deficiency results in a complete lack of segregated nucleus-containing atypical monocytes (Ly6C − F4/80 − Mac1 + Ceacam1 + Msr1 + ) derived from Ly6C − Fc ε RI + granulocyte/macrophage progenitors, preventing the development of bleomycin-induced lung fibrosis [ 190 ]. Moreover, high C/EBP β levels in monocyte-derived alveolar macrophages, but not tissue-resident alveolar macrophages, promotes lung fibrosis [ 42 , 214 ]. During lung injury, the stress response protein Trib3 in monocyte-derived alveolar macrophages interacts with GSK-3 β and protects it from ubiquitination and degradation [ 214 ].…”

LncRNA DACH1 protects against pulmonary fibrosis by binding to SRSF1 to suppress CTNNB1 accumulation

“…Pulmonary fibrosis is the end-stage outcome of a large variety of lung diseases characterized by excessive fibroblast proliferation, aberrant extracellular matrix (ECM) deposition with inflammatory injury, and destruction of tissue structure 1 . The most common disease type is idiopathic pulmonary fibrosis (IPF), a severe interstitial lung disease that leads to progressive loss of lung function, resulting in significant medical burden due to its severe clinical manifestations, poor prognosis, and high mortality 2 .…”