Cellular stress induces Bax-regulated nuclear bubble budding and rupture followed by nuclear protein release

Lindenboim, Liora; Sasson, Tiki; Worman, Howard J.; Borner, Christoph; Stein, Reuven

doi:10.4161/19491034.2014.970105

Cited by 17 publications

(29 citation statements)

References 56 publications

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“…After various treatments, cells were fixed and stained with different antibodies and Hoechst 33258 dye, as described previously 55 . For mitochondrial staining, cells were incubated with 100 nM MitoTracker Red (Thermo Fisher Scientific, MA, USA) for 15 min at 37°C before fixation, as described 9 . Fluorescent images were captured using a fluorescence microscope (EVOS Cell Imaging Systems, Thermo Fisher Scientific, MA, USA) or confocal microscope (LEICA TCS SP5 II) using Zeiss X63 NA 1.4 objective lens.…”

Section: Transfectionmentioning

confidence: 99%

“…SIGRUNB can be repetitive and ultimately lead to the discharge of nuclear proteins into the cytoplasm. It precedes morphological changes of apoptosis, occurs independently of caspases and cytochrome c release and is not inhibited by Bcl-x L 9 .…”

Section: Introductionmentioning

confidence: 99%

“…This process involves Bax-regulated disturbances in NE proteins, including lamin A/C, which results in the generation and subsequent rupture of nuclear protein-containing bubbles encapsulated by nuclear pore-depleted NE. We termed this process "stress-induced generation and rupture of nuclear bubbles" (SIGRUNB) 9 . SIGRUNB can be repetitive and ultimately lead to the discharge of nuclear proteins into the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

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Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins

et al. 2020

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The canonical function of Bcl-2 family proteins is to regulate mitochondrial membrane integrity. In response to apoptotic signals the multi-domain pro-apoptotic proteins Bax and Bak are activated and perforate the mitochondrial outer membrane by a mechanism which is inhibited by their interaction with pro-survival members of the family. However, other studies have shown that Bax and Bak may have additional, non-canonical functions, which include stress-induced nuclear envelope rupture and discharge of nuclear proteins into the cytosol. We show here that the apoptotic stimuli cisplatin and staurosporine induce a Bax/Bak-dependent degradation and subcellular redistribution of nesprin-1 and nesprin-2 but not nesprin-3, of the linker of nucleoskeleton and cytoskeleton (LINC) complex. The degradation and redistribution were caspase-independent and did not occur in Bax/Bak double knockout (DKO) mouse embryo fibroblasts (MEFs). Re-expression of Bax in Bax/Bak DKO MEFs restored stress-induced redistribution of nesprin-2 by a mechanism which requires Bax membrane localization and integrity of the α helices 5/6, and the Bcl-2 homology 3 (BH3) domain. We found that nesprin-2 interacts with Bax in close proximity to perinuclear mitochondria in mouse and human cells. This interaction requires the mitochondrial targeting and N-terminal region but not the BH3 domain of Bax. Our results identify nesprin-2 as a Bax binding partner and also a new function of Bax in impairing the integrity of the LINC complex.

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Section: Transfectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins

et al. 2020

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“…Hodgkin and Reed-Sternberg cells show lamin A/C expression [ 33 ] and impaired lamin A/C structure, which is dissimilar from unstimulated common lymphocytes [ 17 ]. It has been described a caspase-dependent and independent [ 224 ] cleavage of lamin A/C, which dismantles the nuclear lamina, and promotes apoptosis in B cell lymphomas [ 225 , 226 ].…”

Section: Figurementioning

confidence: 99%

Lamin A/C and the Immune System: One Intermediate Filament, Many Faces

Saéz

Herrero‐Fernández

Gómez-Bris

et al. 2020

IJMS

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Nuclear envelope lamin A/C proteins are a major component of the mammalian nuclear lamina, a dense fibrous protein meshwork located in the nuclear interior. Lamin A/C proteins regulate nuclear mechanics and structure and control cellular signaling, gene transcription, epigenetic regulation, cell cycle progression, cell differentiation, and cell migration. The immune system is composed of the innate and adaptive branches. Innate immunity is mediated by myeloid cells such as neutrophils, macrophages, and dendritic cells. These cells produce a rapid and nonspecific response through phagocytosis, cytokine production, and complement activation, as well as activating adaptive immunity. Specific adaptive immunity is activated by antigen presentation by antigen presenting cells (APCs) and the cytokine microenvironment, and is mainly mediated by the cellular functions of T cells and the production of antibodies by B cells. Unlike most cell types, immune cells regulate their lamin A/C protein expression relatively rapidly to exert their functions, with expression increasing in macrophages, reducing in neutrophils, and increasing transiently in T cells. In this review, we discuss and summarize studies that have addressed the role played by lamin A/C in the functions of innate and adaptive immune cells in the context of human inflammatory and autoimmune diseases, pathogen infections, and cancer.

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“…Considered together, these results support the hypothesis that intranuclear PKR activation in the conditions of our experiments might require Env- and CD4-mediated fusion or hemifusion of intracellular membranes. Despite this evidence, other viral and cellular proteins including Vpr can initiate nuclear pore defects (de Noronha et al, 2001; Hatch and Hetzer, 2014; Roshal et al, 2003), and nuclear pore breachments occur in proapoptotic cells (Lindenboim et al, 2010; Lindenboim et al, 2014) and in cells infected by other viruses (Chang et al, 2015; Gustin, 2003; Hatch and Hetzer, 2014; Yarbrough et al, 2014; Younessi et al, 2012). Based on these considerations, we propose that membrane damage induced by HIV-1 LAI may enable or accelerate additional viral and cellular processes including proapoptosis that contribute to the nuclear breachment implied by our data.…”

Section: Resultsmentioning

confidence: 99%

Movements of HIV-1 genomic RNA-APOBEC3F complexes and PKR reveal cytoplasmic and nuclear PKR defenses and HIV-1 evasion strategies

et al. 2016

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APOBEC3 cytidine deaminases and viral genomic RNA (gRNA) occur in virions, polysomes, and cytoplasmic granules, but have not been tracked together. Moreover, gRNA traffic is important, but the factors that move it into granules are unknown. Using in situ hybridization of transfected cells and protein synthesis inhibitors that drive mRNAs between locales, we observed APOBEC3F cotrafficking with gRNA without altering its movements. Whereas cells with little cytoplasmic gRNA were translationally active and accumulated Gag, suprathreshold amounts induced autophosphorylation of the cytoplasmic double-stranded RNA (dsRNA)-dependent protein kinase (PKR), causing eIF2α phosphorylation, protein synthesis suppression, and gRNA sequestration in stress granules. Additionally, we confirmed recent evidence that PKR is activated by chromosome-associated cellular dsRNAs after nuclear membranes disperse in prophase. By arresting cells in G2, HIV-1 blocks this mechanism for PKR activation and eIF2α phosphorylation. However, cytopathic membrane damage in CD4- and coreceptor-positive cultures infected with laboratory-adapted fusogenic HIV-1LAI eventually enabled PKR entry and activation in interphase nuclei. These results reveal multiple stages in the PKR-HIV-1 battleground that culminate in cell death. We discuss evidence suggesting that HIV-1s evolve in vivo to prevent or delay PKR activation by all these mechanisms.

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Cellular stress induces Bax-regulated nuclear bubble budding and rupture followed by nuclear protein release

Cited by 17 publications

References 56 publications

Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins

Apoptotic stress induces Bax-dependent, caspase-independent redistribution of LINC complex nesprins

Lamin A/C and the Immune System: One Intermediate Filament, Many Faces

Movements of HIV-1 genomic RNA-APOBEC3F complexes and PKR reveal cytoplasmic and nuclear PKR defenses and HIV-1 evasion strategies

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