Figure 6. Schematic view of celiac disease pathogenesis.

The P31–43 peptide from the gluten‐associated protein gliadin is generated in the gut lumen and interacts with the NBD1 domain of CFTR, if the domain is in its inactive conformation. P31–43 binds to specific residues of NBD1 of inactive CFTR, competing with ATP binding, thus blocking CFTR function as an anion channel. The inhibition of CFTR disrupts cellular proteostasis through two effects (i) TG2 activation and (ii) BECN1 complex inhibition. This accessorily recruits TG2 to a tripartite complex that stabilizes P31–43 binding to CFTR, thus worsening CFTR inhibition. P31–43‐mediated CFTR inhibition leads to impaired endosomal trafficking, cytoskeleton disassembly, inflammasome activation resulting in IL‐1β secretion, NF‐κB activation, and consequent IL‐15 production. Stressed enterocytes stimulate local inflammation and immune responses against immunodominant gliadin peptides, in particular peptide P56–88, in the context of HLA‐DQ2/DQ8, thus triggering celiac disease. This pathogenic cascade may be theoretically interrupted at two levels, at the apex by CFTR potentiators that prevent P31–43 binding to CFTR (but are poorly active if they are added after P31–43 addition) or by reconstitution of cellular proteostasis by inhibiting TGase or activating the BECN1 complex.