Functional Studies of Plasmodium falciparum’s Prohibitin1 and Prohibitin 2 in Yeast

Chellappan, Savitha; Roy, Subarna; Nagmoti, Jyoti M; Tabassum, Wahida; Hoti, S.L.; Bhattacharyya, Mrinal Kanti; Nina, Praveen Balabaskaran

doi:10.4103/ijmm.ijmm_20_28

Cited by 5 publications

(2 citation statements)

References 16 publications

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“…PHB2’s functionality exhibits a dependence on its location and its interaction with PHB1 in various contexts [ 2 , 37 , 38 ]. In the mitochondria, PHB1 and PHB2 collaborate to create ring complexes that govern critical processes such as cristae regulation, mitophagy, apoptosis, and cell proliferation [ 6 , 39 – 41 ].…”

Section: Discussionmentioning

confidence: 99%

PHB2 promotes SHIP2 ubiquitination via the E3 ligase NEDD4 to regulate AKT signaling in gastric cancer

Xu,

Xiang,

Yang

et al. 2024

J Exp Clin Cancer Res

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Background Prohibitin 2 (PHB2) exhibits opposite functions of promoting or inhibiting tumour across various cancer types. In this study, we aim to investigate its functions and underlying mechanisms in the context of gastric cancer (GC). Methods PHB2 protein expression levels in GC and normal tissues were examined using western blot and immunohistochemistry. PHB2 expression level associations with patient outcomes were examined through Kaplan–Meier plotter analysis utilizing GEO datasets (GSE14210 and GSE29272). The biological role of PHB2 and its subsequent regulatory mechanisms were elucidated in vitro and in vivo. GC cell viability and proliferation were assessed using MTT cell viability analysis, clonogenic assays, and BrdU incorporation assays, while the growth of GC xenografted tumours was measured via IHC staining of Ki67. The interaction among PHB2 and SHIP2, as well as between SHIP2 and NEDD4, was identified through co-immunoprecipitation, GST pull-down assays, and deletion-mapping experiments. SHIP2 ubiquitination and degradation were assessed using cycloheximide treatment, plasmid transfection and co-immunoprecipitation, followed by western blot analysis. Results Our analysis revealed a substantial increase in PHB2 expression in GC tissues compared to adjacent normal tissues. Notably, higher PHB2 levels correlated with poorer patient outcomes, suggesting its clinical relevance. Functionally, silencing PHB2 in GC cells significantly reduced cell proliferation and retarded GC tumour growth, whereas overexpression of PHB2 further enhanced GC cell proliferation. Mechanistically, PHB2 physically interacted with Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) in the cytoplasm of GC cells, thus leading to SHIP2 degradation via its novel E3 ligase NEDD4. It subsequently activated the PI3K/Akt signaling pathway and thus promoted GC cell proliferation. Conclusions Our findings highlight the importance of PHB2 upregulation in driving GC progression and its association with adverse patient outcomes. Understanding the functional impact of PHB2 on GC growth contributes valuable insights into the molecular underpinnings of GC and may pave the way for the development of targeted therapies to improve patient outcomes.

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Section: Discussionmentioning

confidence: 99%

PHB2 promotes SHIP2 ubiquitination via the E3 ligase NEDD4 to regulate AKT signaling in gastric cancer

Xu,

Xiang,

Yang

et al. 2024

J Exp Clin Cancer Res

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“…At the inner mitochondrial membrane, PHB1 and PHB2 are known to form a 1-2 MDa heterodimeric ring-like supra-macromolecular structure (diameter 20-25 nm) and maintain the mitochondrial stability via this PHB1/PHB2 interaction under metabolic stress (10, 11, 13, 15). Recently, a study based on homology modelling and yeast two-hybrid analysis showed that putative Plasmodium PHBs, interact with each other suggesting that they could form super-complexes of heterodimers in Plasmodium , the functional form required for optimum mitochondrial function (17). As evident, PHBs play a crucial part in maintaining the mitochondrial homeostasis supported by various studies as mentioned above.…”

Section: Introductionmentioning

confidence: 99%

Characterization of prohibitins as novel target to block asexual and sexual stage growth of Plasmodium falciparum

Saini

Ngwa

Marothia

et al. 2022

Preprint

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Prohibitins (PHBs) are highly conserved pleiotropic proteins as they have been shown to mediate key cellular functions. Here, we characterize PHBs encoding putative genes of Plasmodium falciparum by exploiting different orthologous models. We demonstrated that PfPHB1 (PF3D7_0829200) and PfPHB2 (PF3D7_1014700) are expressed in asexual and sexual blood stages of the parasite. Immunostaining indicated these proteins as mitochondrial residents as they were found to be localized as punctate foci. We further validated PfPHBs as organellar proteins residing in the Plasmodium mitochondria, where they interact with each other. Functional characterization was done in Saccharomyces cerevisiae orthologous model by expressing PfPHB1 and PfPHB2 in cells harboring respective mutants. The PfPHBs functionally complemented the yeast PHB1 and PHB2 mutants, where the proteins were found to be involved in stabilizing the mitochondrial DNA, retaining mitochondrial integrity and rescuing yeast cell growth. Further, Rocaglamide (Roc-A), a known inhibitor of PHBs and anti-cancerous agent, was tested against PfPHBs and as an antimalarial. Roc-A treatment retarded the growth of PHB1, PHB2, and ethidium bromide petite yeast mutants. Moreover, Roc-A& inhibited growth of yeast PHBs mutants that were functionally complemented with PfPHBs, validating P. falciparum PHBs as one of the molecular targets for Roc-A. Roc-A treatment led to growth inhibition of artemisinin-sensitive (3D7), artemisinin-resistant (R539T) and chloroquine-resistant (RKL-9) parasites in nanomolar ranges. The compound was able to retard gametocyte growth with significant morphological aberrations. Based on our findings, we propose the presence of functional mitochondrial PfPHB1 and PfPHB2 in P. falciparum and their druggability to block parasite growth.

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Characterization of Plasmodium falciparum prohibitins as novel targets to block infection in humans by impairing the growth and transmission of the parasite

Saini

Ngwa

Marothia

et al. 2023

Biochemical Pharmacology

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Functional Studies of Plasmodium falciparum’s Prohibitin1 and Prohibitin 2 in Yeast

Cited by 5 publications

References 16 publications

PHB2 promotes SHIP2 ubiquitination via the E3 ligase NEDD4 to regulate AKT signaling in gastric cancer

PHB2 promotes SHIP2 ubiquitination via the E3 ligase NEDD4 to regulate AKT signaling in gastric cancer

Characterization of prohibitins as novel target to block asexual and sexual stage growth of Plasmodium falciparum

Characterization of Plasmodium falciparum prohibitins as novel targets to block infection in humans by impairing the growth and transmission of the parasite

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