Adapting Proteostasis and Autophagy for Controlling the Pathogenesis of Cystic Fibrosis Lung Disease

Abstract

Cystic fibrosis (CF), a fatal genetic disorder predominant in the Caucasian population, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (Cftr) gene. The most common mutation is the deletion of phenylalanine from the position-508 (F508del-CFTR), resulting in a misfolded-CFTR protein, which is unable to fold, traffic and retain its plasma membrane (PM) localization. The resulting CFTR dysfunction, dysregulates variety of key cellular mechanisms such as chloride ion transport, airway surface liquid (ASL) homeostasis, mucociliary-clearance, inflammatory-oxidative signaling, and proteostasis that includes ubiquitin-proteasome system (UPS) and autophagy. A collective dysregulation of these key homoeostatic mechanisms contributes to the development of chronic obstructive cystic fibrosis lung disease, instead of the classical belief focused exclusively on ion-transport defect. Hence, therapeutic intervention(s) aimed at rescuing chronic CF lung disease needs to correct underlying defect that mediates homeostatic dysfunctions and not just chloride ion transport. Since targeting all the myriad defects individually could be quite challenging, it will be prudent to identify a process which controls almost all disease-promoting processes in the CF airways including underlying CFTR dysfunction. There is emerging experimental and clinical evidence that supports the notion that impaired cellular proteostasis and autophagy plays a central role in regulating pathogenesis of chronic CF lung disease. Thus, correcting the underlying proteostasis and autophagy defect in controlling CF pulmonary disease, primarily via correcting the protein processing defect of F508del-CFTR protein has emerged as a novel intervention strategy. Hence, we discuss here both the rationale and significant therapeutic utility of emerging proteostasis and autophagy modulating drugs/compounds in controlling chronic CF lung disease, where targeted delivery is a critical factor-influencing efficacy.

Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease

“…Proteasome degradation, delivery of ubiquitin-tagged proteins to the endosome and autophagy pathways are tightly inter-related, and imbalance in either may lead to the accumulation of misfolded proteins and cellular dysfunction [23]. This exosomal proteomic-evidenced signature suggests that CF kidney cells adapt to the CFTR defect by upregulating proteasome activity but that, concomitantly, autophagy and endosomal targeting is impaired as also observed in respiratory cells.…”

“…Downregulation of proteins involved in phagosome maturation, such as RAB-34 and RAB-20 [21], suggest a defective autophagy, as already described in epithelial F508del respiratory cells [22]. Very interestingly, in the respiratory epithelial cell, the proposed mechanism for defective autophagy involves accumulation of transglutaminases (TGMs) which crosslink Beclin-1, an important protein of the autophagosome, and hence decrease the formation of autophagosomes [23,24]. In the present study, the increased expression of TGM1 and TGM3 supports this hypothesis.…”

Roles of Specialized Pro-Resolving Lipid Mediators in Autophagy and Inflammation

“…These effects may be improved using the recently introduced combination cysteamine-amiodarone as autophagy inducers [148]. Other potential pharmacological treatments for CF based on autophagy correction were recently reviewed by Bodas et al [149]. Although none of these treatments have yet reached the bedside, probably due to the high doses required and for the many off-target effects, approaches to restore autophagy and resolution of inflammation in CF can be potentially relevant.…”

Nanomedicine Approaches for the Pulmonary Treatment of Cystic Fibrosis

“…Thus, novel intervention strategies aim to correct the underlying proteostasis and autophagy impairments by rescuing F508del-CFTR to the PM. Lately, studies on proteostasis modulators and autophagy inducers reported encouraging results in preclinical phases (Bodas and Vij, 2019). Cysteamine, a proteostasis regulator FDA-approved 30 years ago for nephropathic cystinosis, has shown promising results in CF treatment (Charrier et al, 2014).…”