TY - JOUR
T1 - Bik reduces hyperplastic cells by increasing Bak and activating DAPk1 to juxtapose ER and mitochondria
AU - Mebratu, Yohannes A.
AU - Leyva-Baca, Ivan
AU - Wathelet, Marc G.
AU - Lacey, Neal
AU - Chand, Hitendra S.
AU - Choi, Augustine M.K.
AU - Tesfaigzi, Yohannes
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-00975-w
DO - 10.1038/s41467-017-00975-w
M3 - Article
C2 - 28986568
AN - SCOPUS:85030787620
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 803
ER -