The anti-apoptotic proteins NAF-1 and iASPP interact to drive apoptosis in cancer cells

Iosub-Amir, Anat; Bai, Fang; Sohn, Yang-Sung; Song, Liang; Tamir, Sagi; Marjault, Henri‐Baptiste; Mayer, Guy; Jennings, Patricia A.; Mittler, Ron; Onuchic, José N.; Friedler, Assaf; Nechushtai, Rachel

doi:10.1039/c8sc03390k

Cited by 11 publications

(11 citation statements)

References 53 publications

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“…Investigations are underway to identify those residues in the secondary coordination sphere that might be involved in the stabilization of the CISD2 cluster in the presence of oxygen and its low pH dependency. Interestingly, induction of apoptosis in breast cancer cells leads to CISD2 interaction with the inhibitor of apoptosis-stimulating protein of p53 (iASPP) and a structural model of holo-CISD2 in interaction with iASPP has been proposed [ 31 ]. Prohibition of this interaction by a iASPP-derived peptide also inhibits apoptosis in these cells.…”

Section: Discussionmentioning

confidence: 99%

New Insights of the NEET Protein CISD2 Reveals Distinct Features Compared to Its Close Mitochondrial Homolog mitoNEET

et al. 2021

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Human CISD2 and mitoNEET are two NEET proteins anchored in the endoplasmic reticulum and mitochondria membranes respectively, with an Fe–S containing domain stretching out in the cytosol. Their cytosolic domains are close in sequence and structure. In the present study, combining cellular and biochemical approaches, we compared both proteins in order to possibly identify specific roles and mechanisms of action in the cell. We show that both proteins exhibit a high intrinsic stability and a sensitivity of their cluster to oxygen. In contrast, they differ in according to expression profiles in tissues and intracellular half-life. The stability of their Fe–S cluster and its ability to be transferred in vitro are affected differently by pH variations in a physiological and pathological range for cytosolic pH. Finally, we question a possible role for CISD2 in cellular Fe–S cluster trafficking. In conclusion, our work highlights unexpected major differences in the cellular and biochemical features between these two structurally close NEET proteins.

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Section: Discussionmentioning

confidence: 99%

New Insights of the NEET Protein CISD2 Reveals Distinct Features Compared to Its Close Mitochondrial Homolog mitoNEET

et al. 2021

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“…In a recent study, Iosub-Amir and colleagues reported that the NAF1 protein regulates apoptosis through the interaction with the iASPP peptide. It is possible that the increase of the NAF1 gene expression induces the apoptosis that in turn could favor the elimination of defective spermatozoa [ 57 ]. In our study, we observed that the A allele of rs7675998 is associated with an increased percentage of normal sperm suggesting that activation of the apoptotic process could increase the percentage of normal spermatozoa.…”

Section: Discussionmentioning

confidence: 99%

Telomere Length and Male Fertility

Gentiluomo

Luddi

Cingolani

et al. 2021

IJMS

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Over the past decade, telomeres have attracted increasing attention due to the role they play in human fertility. However, conflicting results have been reported on the possible association between sperm telomere length (STL) and leukocyte telomere length (LTL) and the quality of the sperm parameters. The aim of this study was to run a comprehensive study to investigate the role of STL and LTL in male spermatogenesis and infertility. Moreover, the association between the sperm parameters and 11 candidate single nucleotide polymorphisms (SNPs), identified in the literature for their association with telomere length (TL), was investigated. We observed no associations between sperm parameters and STL nor LTL. For the individual SNPs, we observed five statistically significant associations with sperm parameters: considering a p < 0.05. Namely, ACYP2˗rs11125529 and decreased sperm motility (p = 0.03); PXK˗rs6772228 with a lower sperm count (p = 0.02); NAF1˗rs7675998 with increased probability of having abnormal acrosomes (p = 0.03) and abnormal flagellum (p = 0.04); ZNF208˗rs8105767 and reduction of sperms with normal heads (p = 0.009). This study suggests a moderate involvement of telomere length in male fertility; however, in our analyses four SNPs were weakly associated with sperm variables, suggesting the SNPs to be pleiotropic and involved in other regulatory mechanisms independent of telomere homeostasis, but involved in the spermatogenic process.

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“…Because iASPP is the only interacting partner of the p53 linker domain, using the p53 Linker‐derived peptides can specifically target iASPP and no other proteins in the apoptotic cascade. The RT loop of iASPP plays a major role in the iASPP auto‐activation mechanism, and was found to be an interaction site between iASPP and NAF‐1 in promoting apoptosis in cancer cells . The iASPP RT is thus a “hot spot” on iASPP that can be targeted in order to inhibit iASPP activity in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Targeting an Interaction Between Two Disordered Domains by Using a Designed Peptide

Mayer

Shpilt

Bressler

et al. 2020

Chemistry A European J

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Intrinsically disordered regions in proteins (IDRs) mediate many disease‐related protein–protein interactions. However, the unfolded character and continuous conformational changes of IDRs make them difficult to target for therapeutic purposes. Here, we show that a designed peptide based on the disordered p53 linker domain can be used to target a partner IDR from the anti‐apoptotic iASPP protein, promoting apoptosis of cancer cells. The p53 linker forms a hairpin‐like structure with its two termini in close proximity. We designed a peptide derived from the disordered termini without the hairpin, designated as p53 LinkTer. The LinkTer peptide binds the disordered RT loop of iASPP with the same affinity as the parent p53 linker peptide, and inhibits the p53–iASPP interaction in vitro. The LinkTer peptide shows increased stability to proteolysis, penetrates cancer cells, causes nuclei shrinkage, and compromises the viability of cells. We conclude that a designed peptide comprising only the IDR from a peptide sequence can serve as an improved inhibitor since it binds its target protein without the need for pre‐folding, paving the way for therapeutic targeting of IDRs.

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The anti-apoptotic proteins NAF-1 and iASPP interact to drive apoptosis in cancer cells

Cited by 11 publications

References 53 publications

New Insights of the NEET Protein CISD2 Reveals Distinct Features Compared to Its Close Mitochondrial Homolog mitoNEET

New Insights of the NEET Protein CISD2 Reveals Distinct Features Compared to Its Close Mitochondrial Homolog mitoNEET

Telomere Length and Male Fertility

Targeting an Interaction Between Two Disordered Domains by Using a Designed Peptide

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