title: Active Bax and Bak are functional holins.
abstract: The mechanism of Bax/Bak-dependent mitochondrial outer membrane permeabilization (MOMP), a central apoptotic event primarily controlled by the Bcl-2 family proteins, remains not well understood. Here, we express active Bax/Bak in bacteria, the putative origin of mitochondria, and examine their functional similarities to the λ bacteriophage (λ) holin. As critical effectors for bacterial lysis, holin oligomers form membrane lesions, through which endolysin, a muralytic enzyme, escapes the cytoplasm to attack the cell wall at the end of the infection cycle. We found that active Bax/Bak, but not any other Bcl-2 family protein, displays holin behavior, causing bacterial lysis by releasing endolysin in an oligomerization-dependent manner. Strikingly, replacing the holin gene with active alleles of Bax/Bak results in plaque-forming phages. Furthermore, we provide evidence that active Bax produces large membrane holes, the size of which is controlled by structural elements of Bax. Notably, lysis by active Bax is inhibited by Bcl-xL, and the lysis activity of the wild-type Bax is stimulated by a BH3-only protein. Together, these results mechanistically link MOMP to holin-mediated hole formation in the bacterial plasma membrane.
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, USA.
authors: Xiaming
authors: X
authors: Pang
authors: Samir H
authors: SH
authors: Moussa
authors: Natalie M
authors: NM
authors: Targy
authors: Jeffrey L
authors: JL
authors: Bose
authors: Nicholas M
authors: NM
authors: George
authors: Casey
authors: C
authors: Gries
authors: Hernando
authors: H
authors: Lopez
authors: Liqiang
authors: L
authors: Zhang
authors: Kenneth W
authors: KW
authors: Bayles
authors: Ry
authors: R
authors: Young
authors: Xu
authors: X
authors: Luo
mesh_terms: D017209:Apoptosis / Q000502:physiology; D010582:Bacteriophage lambda / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics; D016679:Genome, Viral / Q000235:genetics; D009154:Mutation; D018272:Porins / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics* / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018272:Porins; D014764:Viral Proteins; C082001:bacteriophage lambda lysis effector protein S105; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein