title: Cellular stress induces Bax-regulated nuclear bubble budding and rupture followed by nuclear protein release.
abstract: Cellular stress triggers many pathways including nuclear protein redistribution. We previously discovered that this process is regulated by Bax but the underlying mechanism has not yet been studied. Here we define this mechanism by showing that apoptotic stimuli cause Bax-regulated disturbances in lamin A/C and nuclear envelope (NE)-associated proteins which results in the generation and subsequent rupture of nuclear protein-containing bubbles. The bubbles do not contain DNA and are encapsulated by impaired nuclear pore-depleted NE. Stress-induced generation and rupture of nuclear bubbles ultimately leads to the discharge of nuclear proteins into the cytoplasm. This process precedes morphological changes of apoptosis and occurs independently of caspases. Rescue experiments revealed that this Bax effect is non-canonical, i.e. it requires the BH3 domain and α-helices 5 and 6 but it is not inhibited by Bcl(-)xL. Targeting Bax to the NE by the Klarsicht/ANC-1/Syne-1 homology (KASH) domain effectively triggers the generation and rupture of nuclear bubbles. Overall, our findings provide evidence for a novel stress-response, which is regulated by a non-canonical action of Bax on the NE.
authors.affiliation: a Department of Neurobiology; George S. Wise Faculty of Life Sciences ; Tel Aviv University ; Ramat Aviv , Israel.
authors.forename: Liora
authors.initials: L
authors.lastname: Lindenboim
authors.forename: Tiki
authors.initials: T
authors.lastname: Sasson
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
authors.forename: Christoph
authors.initials: C
authors.lastname: Borner
authors.forename: Reuven
authors.initials: R
authors.lastname: Stein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism; D058948:Cell Tracking; D004622:Embryo, Mammalian; D005347:Fibroblasts; D018507:Gene Expression Regulation, Developmental; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009685:Nuclear Envelope / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis; D010750:Phosphoproteins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000235:genetics* / Q000378:metabolism; D000097796:Nucleolin
chemical_list: D034904:Lamin Type A; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D051028:bcl-2-Associated X Protein; D000097796:Nucleolin
keywords: Bax; Bax/Bak, Bax and Bak; DKO, double knockout; INM, inner nuclear membrane; KASH, Klarsicht: ANC-1, Syne homology; LAP, lamina-associated polypeptide; LINC, links nucleoskeleton and cytoskeleton; MEFs, mouse embryonic fibroblasts; MOMP, mitochondrial outer membrane permeabilization; NE, nuclear envelope; NPCs, nuclear pore complexes; NPM, nucleophosmin; NPR, nuclear protein redistribution; ONM, outer nuclear membrane; PI, propidium iodide; Q-VD-OPH, quinoline-Val-Asp(OMe)-CH2-OPH.; SIGRUNB, stress-induced generation and rupture of nuclear bubbles; apoptosis; lamin; nuclear envelope; nucleus