Bik reduces hyperplastic cells by increasing Bak and activating DAPk1 to juxtapose ER and mitochondria

• Published in: Nature communications 2017-10, Vol.8 (1), p.803-14, Article 803
• Main Authors: Mebratu, Yohannes A., Leyva-Baca, Ivan, Wathelet, Marc G., Lacey, Neal, Chand, Hitendra S., Choi, Augustine M. K., Tesfaigzi, Yohannes
• Format: Article
• Language: English
• Subjects: 631/80/642/1463; 631/80/642/333; 631/80/82/23; 631/80/86/1999; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Allergens; Allergens - pharmacology; Animals; Apoptosis; Apoptosis Regulatory Proteins - pharmacology; bcl-2 Homologous Antagonist-Killer Protein - metabolism; Bcl-2 protein; Calcium; Calcium (mitochondrial); Calcium (reticular); Calcium - metabolism; Calcium influx; Calcium-binding protein; Calmodulin; Cells, Cultured; Cigarette smoke; Death-associated protein kinase; Death-Associated Protein Kinases - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Enrichment; Epithelial cells; Epithelial Cells - metabolism; Extracellular signal-regulated kinase; Humanities and Social Sciences; Humans; Hyperplasia; Hyperplasia - metabolism; Inositol 1,4,5-trisphosphate receptors; Mice; Mice, Knockout; Mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; multidisciplinary; Peptides; Peptides - pharmacology; Proto-Oncogene Proteins c-bcl-2 - metabolism; Respiratory Mucosa - cytology; Respiratory Mucosa - drug effects; Respiratory Mucosa - metabolism; Respiratory tract diseases; Rodents; Science; Science (multidisciplinary); Smoke; Tobacco Products
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00975-w

Bik reduces hyperplastic epithelial cells by releasing calcium from endoplasmic reticulum stores and causing apoptosis, but the detailed mechanisms are not known. Here we report that Bik dissociates the Bak/Bcl-2 complex to enrich for ER-associated Bak and interacts with the kinase domain of DAPk1 to form Bik–DAPk1–ERK1/2–Bak complex. Bik also disrupts the Bcl2–IP 3 R interaction to cause ER Ca 2+ release. The ER-associated Bak interacts with the kinase and calmodulin domains of DAPk1 to increase the contact sites of ER and mitochondria, and facilitate ER Ca 2+ uptake by mitochondria. Although the Bik BH3 helix was sufficient to enrich for ER-Bak and elicit ER Ca 2+ release, Bik-induced mitochondrial Ca 2+ uptake is blocked with reduced Bak levels. Further, the Bik-derived peptide reduces allergen- and cigarette smoke-induced mucous cell hyperplasia in mice and in differentiated primary human airway epithelial cultures. Therefore, Bik peptides may have therapeutic potential in airway diseases associated with chronic mucous hypersecretion. Bcl-2 interacting killer (Bik) decreases airway epithelial hyperplasia via apoptosis mediated by calcium release from the endoplasmic reticulum (ER), but the mechanism is unclear. Here the authors show that Bik promotes Bak enrichment at the ER to tether mitochondria for efficient calcium transfer.