Protein Folding and the Challenges of Maintaining Endoplasmic Reticulum Proteostasis in Idiopathic Pulmonary Fibrosis

Abstract

Alveolar epithelial type II (AEII) cells are "professional" secretory cells that synthesize and secrete massive quantities of proteins to produce pulmonary surfactant and maintain airway immune defenses. To facilitate this high level of protein synthesis, AEII cells are equipped with an elaborate endoplasmic reticulum (ER) structure and possess an abundance of the machinery needed to fold, assemble, and secrete proteins. However, conditions that suddenly increase the quantity of new proteins entering the ER or that impede the capacity of the ER to fold proteins can cause misfolded or unfolded proteins to accumulate in the ER lumen, also called ER stress. To minimize this stress, AEII cells adapt by (1) reducing the quantity of proteins entering the ER, (2) increasing the amount of protein-folding machinery, and (3) removing misfolded proteins when they accumulate. Although these adaptive responses, aptly named the unfolded protein response, are usually effective in reducing ER stress, chronic aggregation of misfolded proteins is recognized as a hallmark feature of AEII cells in patients with idiopathic pulmonary fibrosis (IPF). Although mutations in surfactant proteins are linked to the development of ER stress in some rare IPF cases, the mechanisms causing protein misfolding in most cases are unknown. In this article, we review the mechanisms regulating ER proteostasis and highlight specific aspects of protein folding and the unfolded protein response that are most vulnerable to failure. Then, we postulate mechanisms other than genetic mutations that might contribute to protein aggregation in the alveolar epithelium of IPF lung.

Transcriptomics, metabolomics and lipidomics of chronically injured alveolar epithelial cells reveals similar features of IPF lung epithelium

“…Moreover, multiple studies have reported altered proteostasis in aging and IPF lungs, associated with accumulation of aggregated misfolded proteins, defective autophagy, ER stress, and declined of proteasome activity (14,20,38). Taken that into consideration, we first used a new molecular rotor detection system to show the intracellular accumulation of misfolded proteins in chronically injured MLE12 cells.…”

“…These changes include decreased ATP production and a shift toward the use of glycolysis as a means for driving cellular metabolism. Similarly, proteostasis collapse has also been described in the lung of patients with IPF, indicating that dysregulation in protein homeostasis is also a feature of human fibrotic lung conditions (38,40,43).…”

“…Chronic exposure to bleomycin impaired cellular proteostasis in AE2 cells. Proteostasis failure and accumulation of damaged proteins have been described in pulmonary fibrosis (38). In order to evaluate whether proteostasis network was altered in our chronic injury model, we first used a recently established molecular rotor to measure intracellular protein aggregation.…”

Mitochondrial Quality Control in Age-Related Pulmonary Fibrosis

“…Lung fibrosis has been associated with high ER stress markers. This inappropriate response to proteostasis alterations leads to the downregulation of PINK1 in AECII through the expression of ATF3, which acts as a transcriptional repressor of PINK1 [51,55,56]. It has been reported that patients with IPF have decreased levels of Parkin expression in isolated lung fibroblasts and myofibroblasts.…”

Causes of Pulmonary Fibrosis in the Elderly

“…To support this function, type II AEC are equipped with an elaborate ER. In IPF, ER stress facilitates fibrotic remodeling through activation of pro-apoptotic pathways [ 43 ].…”