Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak

Einsele‐Scholz, Stephanie; Malmsheimer, Silke; Bertram, Katrin; Stehle, Daniel; Johänning, Janina; Manz, Marianne; Daniel, Peter T.; Gillissen, Bernhard; Schulze‐Osthoff, Klaus; Eßmann, Frank

doi:10.1242/jcs.193946

Cited by 40 publications

(50 citation statements)

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“…c release from enriched mitochondrial fractions derived from Bax −/− Bak −/− MEFs, not even when cBID was added or heat was provided to the reaction mixture. This result contrasts with reports that BOK can trigger the intrinsic apoptotic pathway independently of BAX/BAK . However, neither of those studies provided direct proof of cyt.…”

Section: Discussioncontrasting

confidence: 96%

“…BOK remains an enigmatic and controversial protein among the BCL‐2 members. In accordance with its sequence homology with BAX/BAK, multiple studies, including our own work, demonstrated that BOK promotes intrinsic apoptosis upon overexpression . However, both BAX/BAK‐dependent as well as BAX/BAK‐independent mechanisms have been proposed since .…”

Section: Discussionsupporting

confidence: 52%

“…However, both BAX/BAK‐dependent as well as BAX/BAK‐independent mechanisms have been proposed since . Currently, there is limited evidence for a proapoptotic role for BOK under physiological and pathophysiological conditions, and several studies even point toward protective roles of BOK in certain tissues or in response to specific stressors .…”

Section: Discussionmentioning

confidence: 99%

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The membrane activity of BOK involves formation of large, stable toroidal pores and is promoted by cBID

et al. 2017

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The BCL-2 family members are key regulators of the intrinsic apoptotic pathway, which is defined by permeabilization of the mitochondrial outer membrane by members of the BAX-like subfamily. BOK is classified as a BAX-like protein; however, its (patho-)physiological role remains largely unclear. We therefore assessed the membrane permeabilization potential of C-terminally truncated recombinant BOK, BOK ΔC . We show that BOK ΔC can permeabilize liposomes mimicking the composition of mitochondrial outer membrane, but not of endoplasmic reticulum, forming large and stable pores over time. Importantly, pore formation was enhanced by the presence of cBID and refractory to the addition of antiapoptotic BCL-X L . However, isolated mitochondria from Bax À/À Bak À/À cells were resistant to BOK-induced cytochrome c release, even in the presence of cBID. Taken together, we show that BOK ΔC can permeabilize liposomes, and cooperate with cBID, but its role in directly mediating mitochondrial permeabilization is unclear and may underlie a yet to be determined negative regulation.

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Section: Discussioncontrasting

confidence: 96%

Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

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The membrane activity of BOK involves formation of large, stable toroidal pores and is promoted by cBID

et al. 2017

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“…This study also suggests that Bok deficiency leads to decreased ER stress signaling, potentially through the regulation of calcium release [82]. More recent findings support a selective and distinguishing role for BOK in regulating the apoptotic response to ER and proteasomal stressors, and show evidence that BOK is fully competent to promote MOMP in the absence of BAK/BAX and BH3-only proteins [83] [81]. …”

Section: Figurementioning

confidence: 63%

“…Recent insights into the chemotherapeutic responses of ovarian cancer cells also point to a BAK/BAX-independent role for BOK in mediating MOMP and apoptosis [83]. At present, we have neither structural information nor any details pertaining to how mitochondria may regulate BOK.…”

Section: Figurementioning

confidence: 98%

Physiological and Pharmacological Control of BAK, BAX, and Beyond

Luna-Vargas

Chipuk

2016

Trends in Cell Biology

133

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Cellular commitment to the mitochondrial pathway of apoptosis is accomplished when pro-apoptotic BCL-2 proteins compromise mitochondrial integrity through the process of mitochondrial outer membrane permeabilization (MOMP). For nearly three decades, intensive efforts focused on the identification and interactions of two key pro-apoptotic BCL-2 proteins: BAK and BAX. Indeed, we now have critical insights into which BCL-2 proteins interact with BAK/BAX to either preserve survival or initiate MOMP. In contrast, while mitochondria are targeted by BAK/BAX, a molecular understanding of how these organelles govern BAK/BAX function remains far less clear. Here, we integrate recent mechanistic insights of pro-apoptotic BCL-2 protein function in the context of mitochondrial environment, and discuss current and potential pharmacological opportunities to control MOMP in disease.

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Apoptotic mitochondrial poration by a growing list of pore‐forming BCL‐2 family proteins

Moldoveanu

2023

BioEssays

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The pore‐forming BCL‐2 family proteins are effectors of mitochondrial poration in apoptosis initiation. Two atypical effectors—BOK and truncated BID (tBID)—join the canonical effectors BAK and BAX. Gene knockout revealed developmental phenotypes in the absence the effectors, supporting their roles in vivo. During apoptosis effectors are activated and change shape from dormant monomers to dynamic oligomers that associate with and permeabilize mitochondria. BID is activated by proteolysis, BOK accumulates on inhibition of its degradation by the E3 ligase gp78, while BAK and BAX undergo direct activation by BH3‐only initiators, autoactivation, and crossactivation. Except tBID, effector oligomers on the mitochondria appear as arcs and rings in super‐resolution microscopy images. The BH3‐in‐groove dimers of BAK and BAX, the tBID monomers, and uncharacterized BOK species are the putative building blocks of apoptotic pores. Effectors interact with lipids and bilayers but the mechanism of membrane poration remains elusive. I discuss effector‐mediated mitochondrial poration.

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Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak

Cited by 40 publications

References 0 publications

The membrane activity of BOK involves formation of large, stable toroidal pores and is promoted by cBID

The membrane activity of BOK involves formation of large, stable toroidal pores and is promoted by cBID

Physiological and Pharmacological Control of BAK, BAX, and Beyond

Apoptotic mitochondrial poration by a growing list of pore‐forming BCL‐2 family proteins

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