In the lung, the two major inherited genetic disorders, cystic fibrosis and AAT deficiency, are conformational disorders that are caused by the hereditary expression of mutant alleles of the cystic fibrosis transmembrane conductance regulator (CFTR) and AAT, respectively [
25]. In addition, mutations of the surfactant proteins (SP) C, B, and A have been identified in familial cases of IPF [
3],[
26]. All of these mutations pose a serious challenge for the proteostasis network as they result not only in impaired function of the respective protein but also in ER stress, dysregulated proteasome, and altered autophagy function [
25]-[
27]. The deltaF508CFTR mutant - the most predominant CFTR mutation in cystic fibrosis patients - is characterized by a misfolded CFTR protein which is rapidly degraded by the proteasome and thus fails to translocate to the plasma membrane [
28]. Consequently, modulating the proteostasis network to stabilize folding and trafficking of this CFTR mutant was suggested as a beneficial therapeutic approach in CF [
29]. Loss of functional CFTR has further been associated with defective autophagy and accumulation of aggregated and polyubiquitinated proteins. Restoration of autophagy increased CFTR trafficking to the cell membrane [
15],[
30]. There is also evidence for enhanced ER stress in CF patients as summarized elsewhere [
25], and inactivation of the XBP-1 pathway decreased inflammatory cytokine production in a model of inflamed CF airway linking ER stress to inflammation [
31]. Likewise, in AAT deficiency, misfolded AAT variants fail to exit the ER and are targeted for ERAD. Some AAT variants polymerize and are degraded via autophagy [
25]. Thereby, misfolded AAT accumulates in hepatocytes and cannot be secreted in the bloodstream, which leads to unopposed protease activity in the lung [
30]. Activation of autophagy prevents aggregate toxicity in hepatocytes and reversed liver pathology in a mouse model of AAT deficiency [
30]. Misfolded AAT primarily leads to proteostasis imbalance and ER stress mainly in the liver while the lung phenotype manifests later in life due to unopposed protease activation [
25]. However, as aggregates of mutant AAT were also detected, e.g., in alveolar macrophages, enhanced aggregate clearance by autophagy might also be beneficial in the lung [
30]. Similarly, most of the known mutations of the SP-C and SP-A genes result in abnormal processing, folding, and accumulation of the mutant protein in the ER, possibly triggering ER stress in alveolar epithelial type II cells (AECII). Subsequent induction of apoptosis in the alveolar epithelium may then initiate fibrotic tissue remodeling and chronic inflammatory responses [
26],[
32]. In addition to ER stress, dysfunction of the proteasome and autophagy pathways has been shown for some of the SP-C mutants
in vitro[
33]. The rare hereditary disorder Hermansky-Pudlak syndrome is also characterized by disturbed proteostasis, namely impaired biogenesis of lysosome-related organelles, which contributes to continuous damage and apoptosis of AECII and early onset of pulmonary fibrosis [
34].