Assembly of Bcl-2 into microsomal and outer mitochondrial membranes

Janiak, F; Leber, Brian; Andrews, David W.

doi:10.1016/s0021-9258(17)36960-0

Cited by 107 publications

(30 citation statements)

References 39 publications

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“…1 A; unpublished data). In contrast, Bcl-2, which is reported to be an integral membrane protein (Chen-Levy et al, 1989;Janiak et al, 1994), was found exclusively in the pellet fraction (Fig. 1 D, control).…”

Section: Damage Signals Enhance the Membrane Association Of Bcl-wmentioning

confidence: 79%

Proapoptotic BH3-only proteins trigger membrane integration of prosurvival Bcl-w and neutralize its activity

Wilson-Annan

O’Reilly

Crawford

et al. 2003

The Journal of Cell Biology

104

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Prosurvival Bcl-2–like proteins, like Bcl-w, are thought to function on organelles such as the mitochondrion and to be targeted to them by their hydrophobic COOH-terminal domain. We unexpectedly found, however, that the membrane association of Bcl-w was enhanced during apoptosis. In healthy cells, Bcl-w was loosely attached to the mitochondrial membrane, but it was converted into an integral membrane protein by cytotoxic signals that induce binding of BH3-only proteins, such as Bim, or by the addition of BH3 peptides to lysates. As the structure of Bcl-w has revealed that its COOH-terminal domain occupies the hydrophobic groove where BH3 ligands bind, displacement of that domain by a BH3 ligand would displace the hydrophobic COOH-terminal residues, allowing their insertion into the membrane. To determine whether BH3 ligation is sufficient to induce the enhanced membrane affinity, or to render Bcl-w proapoptotic, we mimicked their complex by tethering the Bim BH3 domain to the NH2 terminus of Bcl-w. The chimera indeed bound avidly to membranes, in a fashion requiring the COOH-terminal domain, but neither promoted nor inhibited apoptosis. These results suggest that ligation of a proapoptotic BH3-only protein alters the conformation of Bcl-w, enhances membrane association, and neutralizes its survival function.

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Section: Damage Signals Enhance the Membrane Association Of Bcl-wmentioning

confidence: 79%

Proapoptotic BH3-only proteins trigger membrane integration of prosurvival Bcl-w and neutralize its activity

Wilson-Annan

O’Reilly

Crawford

et al. 2003

The Journal of Cell Biology

104

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“…CED-9, Bcl-2 (Akao et al, 1994;Chen et al, 1989;de Jong et al, 1994;Hockenbery et al, 1990;Janiak et al, 1994;Krajewski et al, 1993;Nakai et al, 1993;Nguyen et al, 1993), Bcl-x L (Gonzalez-Garcia et al, 1994), Mcl-1 (Wang and Studzinski, 1997;Yang et al, 1995), the BHRF1 Epstein-Barr virus protein (Hickish et al, 1994) and probably other members of the Bcl-2 family are localized to the cytoplasmic surfaces of the nuclear envelope, the endoplasmic reticulum and the outer mitochondrial membrane. However, it must be underlined that only a fraction of Bcl-x L resides on membranes, and that Bax seems to be cytosolic before an apoptotic stimulus, even though both, like most other family members, bear a C-terminal membrane anchor.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial control of apoptosis

Mignotte¹,

Vayssière²

2001

Advances in Cell Aging and Gerontology

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“…The increased levels of ubiquitinated BCL2 promoted by Nef may have further implications for infected cells. BCL2 is found in multiple subcellular compartments, including the endoplasmic reticulum (ER) and the mitochondria (66)(67)(68). ER-associated BCL2 is mainly involved in the regulation of autophagy through its interaction with BECN1, as stated above.…”

Section: Effects Of the Nef-promoted Ubiquitination Of Bcl2 On Autophagy And Apoptosismentioning

confidence: 99%

HIV Nef-mediated Ubiquitination of BCL2: Implications in Autophagy and Apoptosis

et al. 2021

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Ubiquitination is a process that acts upon every step of the HIV replication cycle. The activity, subcellular localization, and stability of HIV dependency factors as well as negative modulators can be affected by ubiquitination. These modifications consequently have an impact on the progression and outcome of infection. Additionally, recent findings suggest new roles for ubiquitination in the interplay between HIV and the cellular environment, specifically in the interactions between HIV, autophagy and apoptosis. On one hand, autophagy is a defense mechanism against HIV that promotes the degradation of the viral protein Gag, likely through ubiquitination. Gag is an essential structural protein that drives virion assembly and release. Interestingly, the ubiquitination of Gag is vital for HIV replication. Hence, this post-translational modification in Gag represents a double-edged sword: necessary for virion biogenesis, but potentially detrimental under conditions of autophagy activation. On the other hand, HIV uses Nef to circumvent autophagy-mediated restriction by promoting the ubiquitination of the autophagy inhibitor BCL2 through Parkin/PRKN. Although the Nef-promoted ubiquitination of BCL2 occurs in both the endoplasmic reticulum (ER) and mitochondria, only ER-associated ubiquitinated BCL2 arrests the progression of autophagy. Importantly, both mitochondrial BCL2 and PRKN are tightly connected to mitochondrial function and apoptosis. Hence, by enhancing the PRKN-mediated ubiquitination of BCL2 at the mitochondria, HIV might promote apoptosis. Moreover, this effect of Nef might account for HIV-associated disorders. In this article, we outline our current knowledge and provide perspectives of how ubiquitination impacts the molecular interactions between HIV, autophagy and apoptosis.

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Assembly of Bcl-2 into microsomal and outer mitochondrial membranes

Cited by 107 publications

References 39 publications

Proapoptotic BH3-only proteins trigger membrane integration of prosurvival Bcl-w and neutralize its activity

Proapoptotic BH3-only proteins trigger membrane integration of prosurvival Bcl-w and neutralize its activity

Mitochondrial control of apoptosis

HIV Nef-mediated Ubiquitination of BCL2: Implications in Autophagy and Apoptosis

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