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

Yohannes A Mebratu,Neal Lacey,Yohannes Tesfaigzi,Augustine M K Choi,Hitendra S Chand,Marc G Wathelet,Ivan Leyva-Baca

doi:10.1038/s41467-017-00975-w

Yohannes A Mebratu, Neal Lacey + Show 5 more

Open Access

https://doi.org/10.1038/s41467-017-00975-w

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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.

Highlights

Bcl-2 interacting killer (Bik) reduces hyperplastic epithelial cells by releasing calcium from endoplasmic reticulum stores and causing apoptosis, but the detailed mechanisms are not known
endoplasmic reticulum (ER) Bak anchors DAPk1 at the ER and increases the sites of contact between ER and mitochondria, so that the ER Ca2+ that is released due to Bik disrupting the Bcl-2/IP3R interaction is transferred to the mitochondria (Fig. 7)
This leads to compromised mitochondrial outer membrane (MOM) integrity, release of cytochrome c, and activation of caspase-induced cell death. These studies show that Bik elicits its proapoptotic function by activating Bak and by causing DAPk1 to assemble the BDEB complex and by binding to the anti-apoptotic Bcl-2 to facilitate ER-Ca2+ release[35,36,37]

Summary

Introduction

Bik reduces hyperplastic epithelial cells by releasing calcium from endoplasmic reticulum stores and causing apoptosis, but the detailed mechanisms are not known. 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. IFN-γ sensitizes airway epithelial cells (AECs) to cell death[6] by increasing expression of the Bcl-2 interacting killer (Bik) and blocking nuclear translocation of ERK1/25. While Ca2+ oscillations support cell survival in part by positively regulating mitochondrial metabolism, prolonged high-amplitude Ca2+ release into mitochondria via the inositol 1,4,5-trisphosphate receptors (IP3Rs)[10] causes Ca2+ overload and apoptosis[11, 12]. Proteins localized to the ER or mitochondria can determine sites of close contact referred to as mitochondria-associated ER membrane. Bcl-2 overexpression prevents the reduction of ER Ca2+ concentrations by its BH4 domain binding the regulatory and coupling domain channel opening[20,21,22,23]

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