PACS2-TRPV1 axis is required for ER-mitochondrial tethering during ER stress and lung fibrosis.
Jessica KnoellShashi ChillappagariLars KnudsenMartina KorfeiRuth DartschDanny JonigkMark P KuehnelKonrad HoetzeneckerAndreas GuentherPoornima MahavadiPublished in: Cellular and molecular life sciences : CMLS (2022)
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 (SPC Δexon4 ) 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.
Keyphrases
- idiopathic pulmonary fibrosis
- endoplasmic reticulum
- interstitial lung disease
- oxidative stress
- neuropathic pain
- estrogen receptor
- breast cancer cells
- randomized controlled trial
- protein protein
- binding protein
- cell death
- signaling pathway
- amino acid
- single cell
- cell proliferation
- emergency department
- stem cells
- electronic health record
- climate change
- blood brain barrier
- small molecule
- transcription factor
- cancer therapy
- spinal cord
- cell therapy
- artificial intelligence
- subarachnoid hemorrhage
- adverse drug