Defective proteostasis in celiac disease as a new therapeutic target

Area of Science:

• Gastroenterology and Immunology
• Molecular Biology
• Proteostasis and Autophagy

Background:

• Cystic fibrosis (CF) results from loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) chloride channel.
• Gliadin-derived peptides, particularly P31-43, inhibit CFTR, leading to gut dysfunction and contributing to celiac disease (CD) pathogenesis.
• CFTR inhibition disrupts ion balance, activates transglutaminase-2 (TGM2), and impairs autophagy, forming a self-amplifying pathogenic loop.

Purpose of the Study:

• To elucidate the molecular mechanisms linking CFTR dysfunction, TGM2 activation, and autophagy impairment in the context of CF and CD.
• To identify gliadin peptides responsible for CFTR inhibition and altered immune responses.
• To explore potential therapeutic targets for CF and CD based on the identified pathogenic pathways.

Main Methods:

• Analysis of CFTR function and its inhibition by gliadin peptides.
• Investigation of TGM2 activation and autophagy modulation in enterocytes.
• Assessment of immune responses to gliadin peptides, including TGM2-mediated deamidation.

Main Results:

• Gliadin peptide P31-43 inhibits CFTR, inducing an "infernal trio" of CFTR inhibition, TGM2 activation, and autophagy impairment.
• This trio locks enterocytes in a pro-inflammatory state, promoting T lymphocyte responses.
• TGM2-deamidated P57-68 becomes fully antigenic, while P31-43 acts as an adjuvant, highlighting gliadin's dual role in immunogenicity.

Conclusions:

• The
• Therapeutic strategies targeting CFTR potentiators, TGM2 inhibitors, and autophagy enhancers may offer novel treatments for both CF and CD.
• These agents could provide near etiological treatments for these enteropathies.