PACS2–TRPV1 axis is required for ER–mitochondrial tethering during ER stress and lung fibrosis

Abstract

Endoplasmic reticulum (ER) and mitochondria (mito) play a vital role in alveolar type II cell (AEC2) homeostasis and are both stressed in patients with idiopathic pulmonary fibrosis (IPF). Up to now, no data are available with regard to ER–mito cross talk and tethering under conditions of IPF. We here demonstrate that ER–mitochondrial tethering is reduced upon experimental ER stress in vitro and in the IPF AECII ex vivo, and this is—at least in part—due to decreased phosphofurin acidic cluster sorting protein 2 (PACS-2, also called PACS2) protein levels. PACS2 levels are influenced by its interaction with the transient receptor potential cation channel subfamily V member 1 (TRPV1) and can be experimentally modified by the TRPV1-modulating drug capsaicin (CPS). Employing alveolar epithelial cells with overexpression of the terminal ER stress signaling factor Chop or the IPF-associated surfactant protein C mutation (SPCΔexon4) in vitro, we observed a restoration of PACS2 levels upon treatment with CPS. Similarly, treatment of precision cut lung slices from IPF patients with CPS ex vivo forwarded similar effects. Importantly, in all models such kind of intervention also greatly reduced the extent of alveolar epithelial apoptosis. We therefore conclude that therapeutic targeting of the PACS2–TRPV1 axis represents an interesting novel, epithelial-protective approach in IPF.

The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis

“…Unlike 14-3-3ε, PACS-2 possesses multiple modes of action on apoptotic pathways, either a positive effect via TRAIL-induced apoptosis, ,, or a negative effect via the regulation of cell growth, DNA damage, and ER stress. ,,, As staurosporine-induced apoptosis is correlated with the upregulation of ER-stress proteins, it was not unexpected that PACS-2 WT overexpression, which directly increases autocrine epidermal growth receptor signaling, decreased apoptosis levels. , However, the presence of PACS-2 E209K sensitized HCT116 cells to staurosporine-induced apoptosis. As PACS-2 E209K has an enhanced interaction with 14-3-3ε, it remains plausible that the abundance of this protein complex alters the regulatory mode of PACS-2 to subsequently promote apoptosis.…”

High-Fat Diet Related Lung Fibrosis-Epigenetic Regulation Matters

“…Endoplasmic reticulum (ER) stress refers to accumulation of unfolded proteins induced by imbalanced protein homeostasis [ 78 ]. Excessive ER stress lead to repetitive damages to epithelial cells and was recently showed to facilitate PF progression [ 1 , 79 ].…”

Advances in cellular senescence in idiopathic pulmonary fibrosis (Review)

“…Liu et al (125) showed that 4-phenylbutyrate, a chemical ER chaperone, ameliorates ER stress, interstitial damage, collagen deposition and apoptosis in unilateral ureteral obstruction rat kidney. Research (126) has demonstrated reduced ER mitochondrial tethering in in vitro experimental ER stress and in vitro IPF ATII experiments in the presence of decreased expression of phospholipase acidic cluster classification protein 2 (PACS2). The levels of PACS2 are affected by its interaction with transient receptor potential cation channel subfamily V member 1 (TRPV1) and can be experimentally modified using capsaicin (CPS) and recovered following CPS treatment.…”

“…The levels of PACS2 are affected by its interaction with transient receptor potential cation channel subfamily V member 1 (TRPV1) and can be experimentally modified using capsaicin (CPS) and recovered following CPS treatment. Thus, therapeutic targeting of the PACS2/TRPV1 axis represents a novel approach to epithelial protection in IPF (126). Some ER stress inhibitors target lung cells and most experiments are in vitro (127,128).…”