Viral Bcl2s’ transmembrane domain interact with host Bcl2 proteins to control cellular apoptosis

García-Murria, Maria Jesús; Duart, Gerard; Grau, Brayan; Diaz-Beneitez, Elisabet; Rodrı́guez, Dolores; Mingarro, Ismael; Martínez-Gil, Luis

doi:10.1038/s41467-020-19881-9

Cited by 16 publications

(25 citation statements)

References 69 publications

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“…Afterwards, we mapped the 365 targets to the CTD database for disease enrichment analysis, thereby obtaining 184 targets associated with gastric cancer (Supplementary Table S2 ). Among the gastric cancer-related targets, B-Cell CLL/Lymphoma 2 (BCL2) 16 , Caspase 3 (CASP3) 17 , interleukin-10 (IL-10), nitric oxide synthase, inducible (NOS2), nuclear factor kappa-B (NFκB), Cyclooxygenase 2 (COX2) 18 and other proteins were involved in the immunoregulation, apoptosis and inflammatory processes of gastrointestinal diseases, which may indicate the synergistic effect of compounds and targets on gastric cancer.…”

Section: Resultsmentioning

confidence: 99%

Systems pharmacology to reveal multi-scale mechanisms of traditional Chinese medicine for gastric cancer

Zhang

Xiao

Yang

et al. 2021

Sci Rep

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Because of the complex etiology, the treatment of gastric cancer is a formidable challenge for contemporary medical. The current treatment method focuses on traditional surgical procedures, supplemented by other treatments. Among these other treatments, Traditional Chinese Medicine (TCM) plays an important role. Here, we used the systems pharmacology approach to reveal the potential molecular mechanism of PRGRC on gastric cancer which composes of Pinellia ternata(Thunb.) Breit., Rheum palmatumL., Gentiana scabraBunge, Radix Aucklandiae and Citrus aurantium L. This approach combines pharmacokinetics analysis with pharmacodynamics evaluation for the active compounds screening, targets prediction and pathways assessing. Firstly, through pharmacokinetic evaluation and target prediction models, 83 potential compounds and 184 gastric cancer-related targets were screened out. Then, the results of network analysis suggested that the targets of PRGRC were mainly involved two aspects: apoptosis and inflammation. Finally, we verified the reliability of the above analysis at the cellular level by using naringenin and luteolin with good pharmacokinetic activity as representative compounds. Overall, we found that PRGRC could influence the development of gastric cancer from a multi-scale perspective. This study provided a new direction for analyzing the mechanism of TCM.

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Section: Resultsmentioning

confidence: 99%

Systems pharmacology to reveal multi-scale mechanisms of traditional Chinese medicine for gastric cancer

Zhang

Xiao

Yang

et al. 2021

Sci Rep

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“…The disparity observed for the BclxL and Bax TMD-TMD interaction could also be attributed to the low expression levels of Bax TMD in 293T cells. Expression of the Bax TMD domain has been shown to induce some toxicity in eukaryotic cells (16,18).…”

Section: Discussionmentioning

confidence: 99%

“…Bcl2 and Mcl-1 can establish intramembrane interactions with other members of the Bcl2 family (16,17). Furthermore, to block apoptosis, viral analogs of Bcl2 proteins must interact through the TMD with cellular Bcl2 members (18). We sought to explore whether the BclxL TMD can be used to establish interactions with other pro-and anti-apoptotic Bcl2 members.…”

Section: The Tmd Of Bclxl Establishes Interactions With Pro-and Anti-...mentioning

confidence: 99%

“…The reporter signal resulting from a TMD-TMD interaction depends not only on the sequences of the interacting TMDs and thus their inherent affinity, but also on the orientation of the interacting surfaces of the TMDs in relation to their accompanying signaling domains (18,19). To confirm that the lack of interaction between the TMD of BclxL and the TMDs of Bik and Bmf was not the result of misaligned reporter domains (19) we tested opposing combinations of BLaTM chimeras, i.e., βN-Bik/βC-BclxL and βN-Bmf/βC-BclxL (Figure 1d).…”

Section: The Tmd Of Bclxl Establishes Interactions With Pro-and Anti-...mentioning

confidence: 99%

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Computational design of BclxL inhibitors that target transmembrane domain interactions

Duart

Elazar

Weinstein

et al. 2022

Preprint

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Several methods have been developed to explore interactions among water-soluble proteins or regions of proteins. However, techniques to target transmembrane domains have not been examined thoroughly. Here we developed a novel computational approach to design transmembrane sequences that specifically modulate protein-protein interactions in the membrane. To illustrate this method we demonstrated that BclxL can interact with other members of the Bcl2 family through the transmembrane domain and that these interactions are necessary for BclxL control of cell death. Next, we designed sequences that specifically recognize and sequester the transmembrane domain of BclxL. Hence, we were able to prevent BclxL intra-membrane interactions and cancel its anti-apoptotic effect. These results advance our understanding of protein-protein interactions in membranes and provide new means to modulate them. Moreover, the success of our approach may trigger the development of a new generation of inhibitors targeting interactions between transmembrane domains.

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“…Theoretically, the transition between other compartments and the mitochondria is also conceivable. To the ER, BCL-2 proteins could pass through the cytosol via retrotranslocation on the one hand and via lateral sorting from the mitochondria on the other hand [33,34]. In principle, it remains open whether BCL-2 proteins can be transported exclusively via the cytosol or also directly between different compartments.…”

Section: Dynamic Retrotranslocation Determines the Effective Bcl-2 Pr...mentioning

confidence: 99%

How Do Hexokinases Inhibit Receptor-Mediated Apoptosis?

Schoeniger

Wolf

Edlich

2022

Biology

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The regulated cell death apoptosis enables redundant or compromised cells in ontogeny and homeostasis to remove themselves receptor-dependent after extrinsic signaling or after internal stress by BCL-2 proteins on the outer mitochondrial membrane (OMM). Mitochondrial BCL-2 proteins are also often needed for receptor-mediated signaling in apoptosis. Then, the truncated BH3-only protein BID (tBID) blocks retrotranslocation of the pro-apoptotic BCL-2 proteins BAX and BAK from the mitochondria into the cytosol. BAX and BAK in turn permeabilize the OMM. Although the BCL-2 proteins are controlled by a complex regulatory network, a specific mechanism for the inhibition of tBID remained unknown. Curiously, it was suggested that hexokinases, which channel glucose into the metabolism, have an intriguing function in the regulation of apoptosis. Recent analysis of transient hexokinase interactions with BAX revealed its participation in the inhibition of BAX and also BAK by retrotranslocation from mitochondria to the cytosol. In contrast to general apoptosis inhibition by anti-apoptotic BCL-2 proteins, hexokinase I and hexokinase 2 specifically inhibit tBID and thus the mitochondrial apoptosis pathway in response to death receptor signaling. Mitochondrial hexokinase localization and BH3 binding of cytosolic hexokinase domains are prerequisites for protection against receptor-mediated cell death, whereas glucose metabolism is not. This mechanism protects cells from apoptosis induced by cytotoxic T cells.

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Viral Bcl2s’ transmembrane domain interact with host Bcl2 proteins to control cellular apoptosis

Cited by 16 publications

References 69 publications

Systems pharmacology to reveal multi-scale mechanisms of traditional Chinese medicine for gastric cancer

Systems pharmacology to reveal multi-scale mechanisms of traditional Chinese medicine for gastric cancer

Computational design of BclxL inhibitors that target transmembrane domain interactions

How Do Hexokinases Inhibit Receptor-Mediated Apoptosis?

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