TRIB3 promotes pulmonary fibrosis through inhibiting SLUG degradation by physically interacting with MDM2

Pulmonary fibrosis(PF)is the pathological structure of incurable fibroproliferative lung diseases that are attributed to the repeated lung injury-caused failure of lung alveolar regeneration(LAR).Here,we report that repetitive lung damage results in a progressive accumulation of the transcriptional repressor SLUG in alveolar epithelial type II cells(AEC2s).The abnormal increased SLUG inhibits AEC2s from self-renewal and differentiation into alveolar epithelial type I cells(AEC1s).We found that the elevated SLUG represses the expression of the phosphate transporter SLC34A2 in AEC2s,which reduces intracellular phosphate and represses the phosphorylation of JNK and P38 MAPK,two critical kinases supporting LAR,leading to LAR failure.TRIB3,a stress sensor,interacts with the E3 ligase MDM2 to suppress SLUG degradation in AEC2s by impeding MDM2-catalyzed SLUG ubiquitination.Targeting SLUG degradation by disturbing the TRIB3/MDM2 interaction using a new synthetic staple peptide restores LAR capacity and exhibits potent therapeutic efficacy against experimental PF.Our study reveals a mechanism of the TRIB3—MDM2—SLUG—SLC34A2 axis causing the LAR failure in PF,which confers a potential strategy for treating patients with fibroproliferative lung diseases.

Highlights of the 2nd International Symposium on Tribbles and Diseases: tribbles tremble in therapeutics for immunity, metabolism, fundamental cell biology and cancer

The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.

The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration

The cell cycle inhibitor P21 has been implicated in cell senescence and plays an important role in the injury-repair process following lung injury.Pulmonary fibrosis(PF)is a fibrotic lung disorder characterized by cell senescence in lung alveolar epithelial cells.In this study,we report that P21 expression was increased in alveolar epithelial type 2 cells(AEC2 s)in a time-dependent manner following multiple bleomycin-induced PF.Repeated injury of AEC2 s resulted in telomere shortening and triggered P21-dependent cell senescence.AEC2 s with elevated expression of P21 lost their self-renewal and differentiation abilities.In particular,elevated P21 not only induced cell cycle arrest in AEC2 s but also bound to P300 andβ-catenin and inhibited AEC2 differentiation by disturbing the P300-β-catenin interaction.Meanwhile,senescent AEC2 s triggered myofibroblast activation by releasing profibrotic cytokines.Knockdown of P21 restored AEC2-mediated lung alveolar regeneration in mice with chronic PF.The results of our study reveal a mechanism of P21-mediated lung regeneration failure during PF development,which suggests a potential strategy for the treatment of fibrotic lung diseases.