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

Yohannes A. Mebratu, Ivan Leyva-Baca, Marc G. Wathelet, Neal Lacey, Hitendra S. Chand, Augustine M. K. Choi and Yohannes Tesfaigzi ()
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Yohannes A. Mebratu: COPD Program, Lovelace Respiratory Research Institute
Ivan Leyva-Baca: COPD Program, Lovelace Respiratory Research Institute
Marc G. Wathelet: Infectious Diseases Program, Lovelace Respiratory Research Institute
Neal Lacey: COPD Program, Lovelace Respiratory Research Institute
Hitendra S. Chand: COPD Program, Lovelace Respiratory Research Institute
Augustine M. K. Choi: Weill Cornell Medical Center
Yohannes Tesfaigzi: COPD Program, Lovelace Respiratory Research Institute

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract 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–IP3R interaction to cause ER Ca2+ 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 Ca2+ uptake by mitochondria. Although the Bik BH3 helix was sufficient to enrich for ER-Bak and elicit ER Ca2+ release, Bik-induced mitochondrial Ca2+ 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.

Date: 2017
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DOI: 10.1038/s41467-017-00975-w

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