Crosstalk of the IκB Kinase with Spliced X-Box Binding Protein 1 Couples Inflammation with Glucose Metabolic Reprogramming in Epithelial-Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) plays a critical role in airway injury, repair, and structural remodeling. I kappa B kinase (IKK)-NF kappa B signaling regulates late EMT-associated gene expression. However, IKK-mediated mesenchymal transition occurs earlier than NF kappa B/RelA subunit-dependent EMT gene expression, leading us to investigate the hypothesis that IKK plays an independent mechanism in transforming growth factor-beta (TGF beta)-induced EMT. Time-resolved dissection of early proteome and phosphoproteome changes in response to TGF beta and a specific IKK inhibitor, BMS-345541, revealed that IKK regulates cascades of 23 signaling pathways essential in EMT, including TGF beta signaling, p38 mitogen associate protein kinase (MAPK), Toll receptor signaling, and integrin pathways. We identified early IKK-dependent phosphorylation of core regulatory proteins in essential EMT signaling cassettes, including ATF2, JUN, NFKB1/p105, and others. Interestingly, we found that IKK beta directly complexes with and phosphorylates the spliced X-box-binding protein 1 (XBP1s). XBP1s is an arm of the unfolded protein response (UPR) that activates the hexosamine biosynthetic pathway (HBP), a pathway that mediates protein N-glycosylation and survival from ER stress-induced apoptosis in EMT. We found that inhibition of IKK activity abolishes the phosphorylation of XBP1-T48, blocks XBP1s nuclear translocation, and inhibits the activation of HBP. Our study elucidates a previously unrecognized IKK beta-XBP1s-HBP crosstalk pathway that couples inflammation and glucose metabolic reprogramming in ETM. Because XBP1-HBP controls N-glycosylation of the extracellular matrix (ECM) in EMT, this novel IKK beta-XBP1-HBP pathway may contain therapeutic targets whose inhibition could prevent ECM remodeling in lung fibrosis or other airway remodeling diseases.

Automated summary

IKK regulates essential signaling pathways in TGF beta-induced EMT, and a new crosstalk pathway involving IKK, XBP1s and HBP was identified. This pathway controls N-glycosylation of the extracellular matrix in EMT and may hold therapeutic potential for preventing ECM remodeling in lung fibrosis and other airway remodeling diseases.