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A redox switch regulates the structure and function of anti-apoptotic BFL-1.

ABSTRACT: Apoptosis is regulated by BCL-2 family proteins. Anti-apoptotic members suppress cell death by deploying a surface groove to capture the critical BH3 ?-helix of pro-apoptotic members. Cancer cells hijack this mechanism by overexpressing anti-apoptotic BCL-2 family proteins to enforce cellular immortality. We previously identified and harnessed a unique cysteine (C55) in the groove of anti-apoptotic BFL-1 to selectively neutralize its oncogenic activity using a covalent stapled-peptide inhibitor. Here, we find that disulfide bonding between a native cysteine pair at the groove (C55) and C-terminal ?9 helix (C175) of BFL-1 operates as a redox switch to control the accessibility of the anti-apoptotic pocket. Reducing the C55-C175 disulfide triggers ?9 release, which promotes mitochondrial translocation, groove exposure for BH3 interaction and inhibition of mitochondrial permeabilization by pro-apoptotic BAX. C55-C175 disulfide formation in an oxidative cellular environment abrogates the ability of BFL-1 to bind BH3 domains. Thus, we identify a mechanism of conformational control of BFL-1 by an intramolecular redox switch.

SUBMITTER: Korshavn KJ

PROVIDER: S-EPMC7544158 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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A redox switch regulates the structure and function of anti-apoptotic BFL-1.

Korshavn Kyle J KJ Wales Thomas E TE Bird Gregory H GH Engen John R JR Walensky Loren D LD

Nature structural & molecular biology 20200713 9

Apoptosis is regulated by BCL-2 family proteins. Anti-apoptotic members suppress cell death by deploying a surface groove to capture the critical BH3 α-helix of pro-apoptotic members. Cancer cells hijack this mechanism by overexpressing anti-apoptotic BCL-2 family proteins to enforce cellular immortality. We previously identified and harnessed a unique cysteine (C55) in the groove of anti-apoptotic BFL-1 to selectively neutralize its oncogenic activity using a covalent stapled-peptide inhibitor. ...[more]

PMID: 32661419

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Project description:Neutrophil granulocytes are innate effector cells of the first line of defense against pyogenic bacteria. Neutrophil lifespan is short, is prolonged by pro-inflammatory stimuli, controls functionality of the cells and can determine tissue damage. Experimental analysis of primary neutrophils is difficult because of their short lifespan and lack of possibilities of genetic manipulation. The Hoxb8 system of neutrophil differentiation from immortalized progenitor cells offers the advantage of unlimited production of neutrophils in vitro as well as easy genetic modification. We here use this system to analyze the role of the poorly characterized anti-apoptotic B-cell lymphoma protein 2 (Bcl-2) family member A1/Bfl-1 (Bcl-2-related protein A1) for survival and homeostasis of neutrophils and of neutrophil progenitors. Low constitutive mRNA and protein expression of A1 was detected, while A1 was transiently upregulated early during differentiation. Pro-inflammatory stimuli caused strong, mainly transcriptional, A1 upregulation, in contrast to posttranscriptional regulation of Mcl-1 (induced myeloid leukemia cell differentiation protein). Inhibitor studies showed that phosphoinositide-3 kinase (PI3K)/Akt and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) is required for A1 expression and survival of progenitors and mature neutrophils. ShRNA-mediated constitutive A1 knockdown (KD) impaired maintenance of progenitors. ShRNA experiments further showed that A1 was required early during neutrophil differentiation as well as in mature neutrophils upon pro-inflammatory stimulation. Our data further indicate differential regulation of the two anti-apoptotic proteins A1 and Mcl-1. Relevant findings were confirmed in primary human neutrophils. Our data indicate that A1, in addition to the well-established Mcl-1, substantially contributes to neutrophil survival and homeostasis. A1 may thus be a promising target for anti-inflammatory therapy.

Dataset Information

A redox switch regulates the structure and function of anti-apoptotic BFL-1.

Publications

A redox switch regulates the structure and function of anti-apoptotic BFL-1.

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