Involvement of the Prion Protein in the Protection of the Human Bronchial Epithelial Barrier Against Oxidative Stress

Abstract

Aim: Bronchial epithelium acts as a defensive barrier against inhaled pollutants and microorganisms. This barrier is often compromised in inflammatory airway diseases that are characterized by excessive oxidative stress responses, leading to bronchial epithelial shedding, barrier failure, and increased bronchial epithelium permeability. Among proteins expressed in the junctional barrier and participating to the regulation of the response to oxidative and to environmental stresses is the cellular prion protein (PrP C). However, the role of PrP C is still unknown in the bronchial epithelium. Herein, we investigated the cellular mechanisms by which PrP C protein participates into the junctional complexes formation, regulation, and oxidative protection in human bronchial epithelium. Results: Both PrP C mRNA and mature protein were expressed in human epithelial bronchial cells. PrP C was localized in the apical domain and became lateral, at high degree of cell polarization, where it co-localized and interacted with adherens (E-cadherin/catenin) and desmosomal (desmoglein/desmoplakin) junctional proteins. No interaction was detected with tight junction proteins. Disruption of such interactions induced the loss of the epithelial barrier. Moreover, we demonstrated that PrP C protection against copper associated oxidative stress was involved in multiple processes, including the stability of adherens and desmosomal junctional proteins. Innovation: PrP C is a pivotal protein in the protection against oxidative stress that is associated with the degradation of adherens and desmosomal junctional proteins. Conclusion: Altogether, these results demonstrate that the loss of the integrity of the epithelial barrier by oxidative stress is attenuated by the activation of PrP C expression, which deregulation might be associated to respiratory diseases.

Junctional complexes in epithelial cells: sentinels for extracellular insults and intracellular homeostasis

“…Desmoplakin mediates the connection between intermediate filaments and the junctional plaque at the cell membrane [17][18][19]. There are also several nonstructural proteins found in desmosomes, such as the RhoA regulator kazrin [76], the LRR And PDZ family scaffolding protein erbb2 interacting protein (Erbin) [77], and the prion protein PrPC [74]. Type I hemidesmosomes comprise a group of transmembrane receptors, including a6b4 integrins, 180-kDa bullous pemphigoid antigen (BP180), and cluster of differentiation 151 (CD151).…”

“…In addition to the core structural components mentioned above, proteins with diverse functions attach to the adherens junctions but are not essential for the assembly of the junctional structure. These molecules include but not limited to the transcriptional coactivator YAP [62] and its regulators (Ajuba family proteins and LATS family proteins) [63,64], the Ras homolog (Rho) guanosine triphosphate hydrolase (GTPase) RhoA [65,66], the Rho guanine nucleotide exchange factor epithelial cell transforming 2 (ECT2) [65], the centralspindlin complex protein male germ cell Rac GTPase-activating protein (MgcRacGAP) [65], Rho-associated protein kinase 1 (ROCK1) [67], tyrosine kinases erythroblastic oncogene B2 (ErbB2) and Fps/Fes [68,69], phosphoinositide 3-kinase (PI3K) [70], the tyrosine phosphatase Pez [71], PTEN [72], Ras association domain family member 8 (RASSF8) [73], the prion protein prolinerich protein C (PrPC) [74] and the mechanoreceptor transient receptor potential cation channel subfamily V member 4 (TRPV4) [75]. The core transmembrane proteins of desmosomes include desmoglein and desmocollin, whose ectodomains interact in a heterophilic or homophilic manner with their partners at the adjacent cell membrane.…”

The Prospective Effect of Cinnamon and Chia on Submandibular Salivary Glands After Ciprofloxacin Administration in Albino Rats (Histological, Histochemical, and Ultrastructural Study)

“…Furthermore, Anding & Baehrecke (2017) spotted using EM that vacuolations were actually damaged organelles such as mitochondria and lysosomes or could be lipid-filled or autophagic vacuoles. Additionally, the oxidative stress disrupts different epithelial intercellular junctions through protein modification “such as thiol oxidation, phosphorylation, nitration, and carbonylation” in addition to degradation of adherens and desmosomal junction proteins (Rao, 2008; Inumaru et al, 2009; Kouadri et al, 2019).…”

Effect of tiger milk mushroom (Lignosus rhinocerus) supplementation on respiratory health, immunity and antioxidant status: an open-label prospective study

“…Similarly, oral administration of TMM in diabetic animal model also found that elevated glutathione (GSH) level, superoxide dismutase (SOD), and catalase (CAT) activities to be associated with reduced lipid peroxidation 66 . Reduced lipid peroxidation is important to prevent many detrimental effects on airway function which were caused by oxidative stress, including airway hyperresponsiveness 67 , mucus hypersecretion 68 , epithelial shedding 69 , airway smooth muscle contraction 70 , vascular exudation 71 , and increased vascular permeability 72 . Our result also revealed that participants with normal BMI responded better to the supplementation as compared to other categories of BMI.…”