BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis

Huang, Kai; O’Neill, Katelyn; Li, Jian; Zhou, Wei; Han, Namshik; Pang, Xiaming; Wu, Wei; Struble, Lucas R.; Borgstahl, Gloria E. O.; Liu, Zhaorui; Zhang, Liqiang; Luo, Xu

doi:10.1038/s41422-019-0231-y

Cited by 101 publications

(108 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It was reported that MTCH2 could facilitate the recruitment of the truncated BID to mitochondria (24). BID could indirectly activate BAX/BAK and thus allowing them to undergo unimpeded, spontaneous activation in the mitochondrial outer membrane, leading to apoptosis initiation (25). Studies have suggested that, when activated, Bak and Bax, create discontinuity or pores in the outer mitochondrial membrane, to mediate the release of Cytochrome C (26).…”

Section: Discussionmentioning

confidence: 99%

Silica nanoparticles inducing the apoptosis of spermatocyte cell through microRNA-450b-3p targeting MTCH2-mediating mitochondrial signaling pathway

Zhou

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Silica nanoparticles (SiNPs) are found in environmental particulate matter and are proven to have adverse effects on fertility. The relationship and underlying mechanisms between miRNAs and apoptosis induced by SiNPs during spermatogenesis is currently ambiguous. Experimental design: The present study was designed to investigate the role of miRNA-450b-3p in the reproductive toxicity caused by SiNPs. In vivo, 40 male mice were randomly divided into control and SiNPs groups, 20 per group. The mice in the SiNPs group were administrated 20 mg/kg SiNPs by tracheal perfusion once every 5 days, for 35 days, and the control group were given the equivalent of a normal luminal saline. In vitro, spermatocyte cells were divided into 0 and 5 μg/mL SiNPs groups, after passaged for 30 generations, the GC-2spd cells in 5 μg/mL SiNPs groups were transfected with miRNA-450b-3p and its mimic and inhibitor. Results: In vivo, the results showed that SiNPs damaged tissue structures of testis, decreased the quantity and quality of the sperm, reduced the expression of miR-450b-3p, and increased the protein expressions of the MTCH2, BID, BAX, Cytochrome C, Caspase-9, and Caspase-3 in the testis. In vitro, SiNPs obviously repressed the viability and increased the LDH level and apoptosis rate, decreased the levels of the miR-450b-3p, significantly enhanced the protein expressions of the MTCH2, BID, BAX, Cytochrome C, Caspase-9, Caspase-3; while the mimic of miR-450b-3p reversed the changes induced by SiNPs, but inhibitor further promoted the effects induced by SiNPs.Conclusion: The result suggested that SiNPs could induce the spermatocyte apoptosis by inhibiting the miR-450b-3p expression to target promoting the MTCH2 resulting in activating mitochondrial apoptotic signaling pathways in the spermatocyte cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Silica nanoparticles inducing the apoptosis of spermatocyte cell through microRNA-450b-3p targeting MTCH2-mediating mitochondrial signaling pathway

Zhou

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…While one would assume that the setting, in which the activation of Bax by BH3-only proteins is required (for the sake of simplicity we will refer to this as to 'activation-requiring' Bax) reflects the situation observed in mammalian cells, recent experiments with knock-out mammalian cells simultaneously lacking all eight genes encoding for BH3-only proteins indicated that even in mammalian cells Bax may be activated by the inhibition of antiapoptotic proteins only when BH3-only proteins are absent [48,49]. Dispensability of BH3-only proteins for Bax activation, thus, appears to correlate with the behaviour of the 'constitutively active' version Bax in yeast.…”

Section: Bax and Bak Activationmentioning

confidence: 99%

Reconstituting the Mammalian Apoptotic Switch in Yeast

Polčic

Mentel

2020

Genes

View full text Add to dashboard Cite

Proteins of the Bcl-2 family regulate the permeabilization of the mitochondrial outer membrane that represents a crucial irreversible step in the process of induction of apoptosis in mammalian cells. The family consists of both proapoptotic proteins that facilitate the membrane permeabilization and antiapoptotic proteins that prevent it in the absence of an apoptotic signal. The molecular mechanisms, by which these proteins interact with each other and with the mitochondrial membranes, however, remain under dispute. Although yeast do not have apparent homologues of these apoptotic regulators, yeast cells expressing mammalian members of the Bcl-2 family have proved to be a valuable model system, in which action of these proteins can be effectively studied. This review focuses on modeling the activity of proapoptotic as well as antiapoptotic proteins of the Bcl-2 family in yeast.

show abstract

“…These studies have shown the Bcl-2 family consists of two phylogenetically distinct groups of proteins: those that share the Bcl-2 fold [90,93] that are either prosurvival or proapoptotic and the proapoptotic intrinsically disordered 'BH3-only' proteins, that bear only the BH3 motif [9]. The BH3-only proteins are upregulated in response to diverse apoptotic stimuli [94] and their principal role is to antagonize the prosurvival proteins [9], but apoptosis also occurs in their absence [95]. Notwithstanding the conservation in the Bcl-2 family, there are substantial differences in Bcl-2-regulated apoptosis mechanisms.…”

Section: Introductionmentioning

confidence: 99%

The Bcl-2 Family: Ancient Origins, Conserved Structures, and Divergent Mechanisms

et al. 2020

View full text Add to dashboard Cite

Intrinsic apoptosis, the response to intracellular cell death stimuli, is regulated by the interplay of the B-cell lymphoma 2 (Bcl-2) family and their membrane interactions. Bcl-2 proteins mediate a number of processes including development, homeostasis, autophagy, and innate and adaptive immune responses and their dysregulation underpins a host of diseases including cancer. The Bcl-2 family is characterized by the presence of conserved sequence motifs called Bcl-2 homology motifs, as well as a transmembrane region, which form the interaction sites and intracellular location mechanism, respectively. Bcl-2 proteins have been recognized in the earliest metazoans including Porifera (sponges), Placozoans, and Cnidarians (e.g., Hydra). A number of viruses have gained Bcl-2 homologs and subvert innate immunity and cellular apoptosis for their replication, but they frequently have very different sequences to their host Bcl-2 analogs. Though most mechanisms of apoptosis initiation converge on activation of caspases that destroy the cell from within, the numerous gene insertions, deletions, and duplications during evolution have led to a divergence in mechanisms of intrinsic apoptosis. Currently, the action of the Bcl-2 family is best understood in vertebrates and nematodes but new insights are emerging from evolutionarily earlier organisms. This review focuses on the mechanisms underpinning the activity of Bcl-2 proteins including their structures and interactions, and how they have changed over the course of evolution.

show abstract

BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis

Cited by 101 publications

References 45 publications

Silica nanoparticles inducing the apoptosis of spermatocyte cell through microRNA-450b-3p targeting MTCH2-mediating mitochondrial signaling pathway

Silica nanoparticles inducing the apoptosis of spermatocyte cell through microRNA-450b-3p targeting MTCH2-mediating mitochondrial signaling pathway

Reconstituting the Mammalian Apoptotic Switch in Yeast

The Bcl-2 Family: Ancient Origins, Conserved Structures, and Divergent Mechanisms

Contact Info

Product

Resources

About