Etiological involvement of CFTR in apparently unrelated human diseases

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-gated channel that regulates anion fluxes across the plasma membrane of multiple cell types. Loss-of-function mutations of CFTR cause the most frequent human monogenetic lethal disease, cystic fibrosis (CF).¹ The pathogenesis of CF involves two complementary phenomena. On one hand, failure to transport chloride anions into the extracellular space increases the viscosity and thickness of mucus, hence compromising its elimination from the respiratory tract (which facilitates chronic inflammation coupled to recurrent pulmonary infections) and the pancreatic ducts (which drives failure of the exocrine pancreas and consequent nutrient malabsorption).¹ On the other hand, imbalances in intracellular anion fluxes (perhaps combined with deficient CFTR scaffold functions) favor a progressive and irreversible imbalance in proteostasis due to activation of transglutaminase 2 (TGM2) and reduced beclin 1 (BECN1) expression, culminating with inhibition of autophagy.^1–4 These three phenomena (deficient CFTR function, TGM2 activation, and autophagy impairment) amplify each other in a feed-forward circuitry, locking affected cells in a close-to-irrevocable pro-inflammatory state that contributes to disease pathogenesis.^5–7 Inhibiting each of the cornerstones of this triad can improve CF pathogenesis, as demonstrated by clinical trials using CFTR-stimulatory agents (so-called “CFTR potentiators”), TGM2 inhibitors, and autophagy enhancers.^8,9 However, it should be noted that the efficacy of these agents is largely dependent on the exact molecular characteristics of the pathogenic CFTR variant. Thus, CFTR potentiators can only improve CFTR functions when the defective protein is expressed on the plasma membrane and possesses residual chloride channel activity. In contrast, cysteamine, a TGM2 inhibitor, and epigallocatechin gallate (EGCG), an autophagy activator,¹⁰ can only synergize at improving CFTR functions if the mutant protein can be rescued from premature degradation or accelerated turnover, thus favoring its reappearance at the plasma membrane.⁹ This effect can also be obtained by so-called “CFTR correctors.” Thus, the precise CFTR defect that accounts for CF (amongst up to 2000 distinct pathogenic CFTR mutations described so far) dictates the pharmacological agents that should be used for the optimal treatment of a specific patient.¹ That said, it appears that patients bearing the most frequent CFTR mutation leading to the deletion of phenylalanine at position 506 (CFTRdel506), which accounts for 70–90% of CF cases, respond well to the combination of EGCG and cysteamine.⁹

Several recent findings suggest that CFTR is not only involved in the pathogenesis of CF, but also contributes to other important human diseases. Thus, CFTR provides an etiological contribution to the pathogenesis of two major autoimmune diseases: (i) autoimmune pancreatitis (AIP), which also affects the exocrine pancreas, and (ii) Sjögren’s syndrome (SS), which is characterized by salivary and lacrimal gland malfunction. At least in specific cases, human AIP is associated with CFTR mutations that affect bicarbonate (HCO₃⁻) but not chloride (Cl⁻) secretion, and thus do not cause CF.¹¹ However, the CFTR dysfunction usually associated with AIP and SS appears to be frequently acquired (rather than inherited). In mouse models closely mimicking human AIP or SS, CFTR expression is markedly reduced in affected organs, and treatment with CFTR correctors and potentiators can restore CFTR expression and plasma membrane localization, dampen inflammation, eliminate tissue damage, and restore fluid secretion.¹² These findings suggest that CFTR is etiologically involved in the pathogenesis of AIP and SS.

Recently, it has also been reported that CFTR is a target of gluten, the cereal substance that causes celiac disease (CD).¹³ CD is an inflammatory and autoimmune condition involving a pathogenic immune response against peptides contained in gliadin (a component of gluten). Indeed, one particular gliadin-derived peptide (P31–43) interacts with the nucleotide-binding domain 1 (NBD1) of CFTR, hence inhibiting its ATPase activity and chloride channel function.¹³ Such an acquired inhibition of CFTR in the intestine drives TGM2 activation and autophagy suppression, in turn favoring local inflammation, reducing gut barrier function, and igniting immune reactions against gliadin. Administration of a pharmacological CFTR potentiator can interrupt this pathogenic cascade and prevent CD in gliadin-sensitive mouse models.¹³ Moreover, stimulation of CFTR function inhibits immune responses driven by gliadin in duodenal biopsies from CD patients. These latter results, coupled to the fact that CF patients have a higher incidence of CD than normal individuals, strongly plead in favor of a pathogenic role for CFTR in CD.¹³

Altogether, these findings suggest that CFTR inhibition is causally involved in several, apparently unrelated diseases, i.e., AIM, CD, CF, and SS (Figure 1). Since CFTR defects have multiple consequences on the intracellular microenvironment that potentially drive disease,¹⁴ it is tempting to speculate that the list of CFTR-related pathologies is not yet exhaustive. Indeed, CF has also been associated with an increased incidence of some neoplasms (such as lung and prostate cancers), reflecting either CFTR mutations or hypermethylation of the CFTR promoter.¹⁵ Beyond this speculation, it appears plausible that inhibition of TGM2 and activation of autophagy will have beneficial effects in all diseases caused by CFTR dysfunction.

Figure 1.

Hypothetical scenario involving CFTR inhibition, TGM2 activation, and autophagy inhibition in several distinct pathologies. CFTR, cystic fibrosis transmembrane conductance regulator; TGM2, transglutaminase 2.

Funding Statement

LG is supported by a Breakthrough Level 2 grant from the US Department of Defense (DoD), Breast Cancer Research Program (BRCP) [#BC180476P1], by a startup grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, USA), by industrial collaborations with Lytix (Oslo, Norway) and Phosplatin (New York, US), and by donations from Phosplatin (New York, US), the Luke Heller TECPR2 Foundation (Boston, US) and Sotio a.s. (Prague, Czech Republic). GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; the European Commission (ArtForce); European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); the European Research Council (ERC); Fondation Carrefour; Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM).

Conflict of interest statement

LG provides remunerated consulting to OmniSEQ (Buffalo, NY, USA), Astra Zeneca (Gaithersburg, MD, USA), VL47 (New York, NY, USA) and the Luke Heller TECPR2 Foundation (Boston, MA, USA), and he is member of the Scientific Advisory Committee of OmniSEQ (Buffalo, NY, USA). GK is a scientific co-founder of Samsara Therapeutics.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.