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. IκB
kinase (IKK)-NFκB signaling regulates late EMT-associated gene
expression. However, IKK-mediated mesenchymal transition occurs earlier
than NFκB/RelA subunit-dependent EMT gene expression, leading
us to investigate the hypothesis that IKK plays an independent mechanism
in transforming growth factor-β (TGFβ)-induced EMT. Time-resolved
dissection of early proteome and phosphoproteome changes in response
to TGFβ and a specific IKK inhibitor, BMS-345541, revealed that
IKK regulates cascades of 23 signaling pathways essential in EMT,
including TGFβ 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 IKKβ 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
IKKβ-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
IKKβ-XBP1-HBP pathway may contain therapeutic targets whose
inhibition could prevent ECM remodeling in lung fibrosis or other
airway remodeling diseases.