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

Abstract

Pulmonary fibrosis (PF) has a high mortality rate, and its pathogenesis is unknown. TNF receptor-associated factor 6 (TRAF6), a signal transducer for inflammatory signaling, plays crucial roles in the pathogenesis of immune diseases. However, its function in PF remains unknown. Herein, we demonstrated that lungs from mice with bleomycin (BLM)-induced PF were characterized by decreased expression of TRAF6 in lung fibroblasts. Enhancing TRAF6 expression protected mice from BLM-induced PF coupled with a significant reduction in fibroblast differentiation. Furthermore, we demonstrated that overexpression of TRAF6 reversed the activation of myofibroblasts from PF mice by reducing the expression of Wnt3a and subsequently suppressing Wnt/β-catenin signaling. Additionally, the abundance of Tribbles pseudokinase 3 (TRIB3), a stress sensor, was negatively correlated with the abundance of TRAF6 in lung fibroblasts. TRIB3 overexpression decreased TRAF6 abundance by reducing TRAF6 stability in lung fibroblasts during PF. Mechanistic studies revealed that TRIB3 bound to TRAF6 and accelerated basal TRAF6 ubiquitination and degradation. Collectively, our data indicate that reduced TRAF6 expression in fibroblasts is essential for the progression of PF, and therefore, genetically increasing TRAF6 expression or disrupting the TRIB3-TRAF6 interaction could be potential therapeutic strategies for fibroproliferative lung diseases in clinical settings.

Tribbles pseudokinase 3 promoted renal fibrosis by regulating the expression of DNA damage-inducible transcript 3 in diabetic nephropathy

“…TRIB3 was considered as a nutrient sensor and influenced energy metabolism by regulating intracellular signaling pathways, including AKT signaling cascade, MAPK pathways, and signaling pathways associated with β-cell apoptosis under heightened nutrient influx, insulin resistance, and elevated blood glucose levels [41][42][43]. TRIB3 has reported to act as a pivotal regulator of crucial cellular processes through its interactions with transcription factors such as CCAAT-enhancer-binding protein homologous protein (CHOP), peroxisome proliferator-activated receptor alpha (PPARα), and activating transcription factor 4 (ATF4), including glucose and lipid metabolism, adipocyte differentiation, autophagy, proteasomal degradation and apoptosis [12,40,44]. Recent report showed that compared to healthy subjects, TRIB3 level was significantly increased in plasma of diabetic patients, and high TRIB3 level was associated with fasting blood glucose and insulin resistance [45].…”

“…Unlike traditional kinases, TRIB3 lacks the canonical adenosine triphosphate (ATP)-binding pocket and catalytic residues, leading to its classification as a pseudokinase. Instead of direct catalytic activity, TRIB3 functions as a molecular scaffold, orchestrating intricate interactions with various transcriptional mediators and signaling molecules [11][12][13]. The dysregulation of TRIB3 gene expression has been linked to several diseases, underscoring its importance in disease pathogenesis.…”