IMPDH2 Is an Intracellular Target of the Cyclophilin A and Sanglifehrin A Complex

Pua, Khian Hong; Stiles, Dylan T.; Sowa, Mathew E.; Verdine, Gregory L.

doi:10.1016/j.celrep.2016.12.030

Cited by 47 publications

(51 citation statements)

References 49 publications

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“…These findings support the notion that the CBS domain plays a key role in mediating cytoophidium assembly. A natural product sanglifehrin A (SFA), has been shown to form a complex with protein cyclophilin A (PPIA) inside human cells [ 50 ]. The PPIA-SFA complex is able to bind with IMPDH2, but not IMPDH1, at the CBS domain and thereby suppress proliferation of lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

IMP/GTP balance modulates cytoophidium assembly and IMPDH activity

et al. 2018

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BackgroundInosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in de novo GTP biosynthesis, plays an important role in cell metabolism and proliferation. It has been demonstrated that IMPDH can aggregate into a macrostructure, termed the cytoophidium, in mammalian cells under a variety of conditions. However, the regulation and function of the cytoophidium are still elusive.ResultsIn this study, we report that spontaneous filamentation of IMPDH is correlated with rapid cell proliferation. Intracellular IMP accumulation promoted cytoophidium assembly, whereas elevated GTP level triggered disassociation of aggregates. By using IMPDH2 CBS domain mutant cell models, which are unable to form the cytoophidium, we have determined that the cytoophidium is of the utmost importance for maintaining the GTP pool and normal cell proliferation in the condition that higher IMPDH activity is required.ConclusionsTogether, our results suggest a novel mechanism whereby cytoophidium assembly upregulates IMPDH activity and mediates guanine nucleotide homeostasis.Electronic supplementary materialThe online version of this article (10.1186/s13008-018-0038-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

IMP/GTP balance modulates cytoophidium assembly and IMPDH activity

et al. 2018

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“…IMPDH2 is believed to be a fascinating target for cancer therapy due to its overexpression particularly in rapidly proliferating and neoplastic cells. A growing number of studies have demonstrated that IMPDH2 was closely implicated in cellular proliferation and tumorigenesis [ 4 , 26 – 28 ]. Herein, we found that IMPDH2 was upregulated at the mRNA and protein level in CRC cell lines, in agreement with a previous study [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

IMPDH2 promotes colorectal cancer progression through activation of the PI3K/AKT/mTOR and PI3K/AKT/FOXO1 signaling pathways

Duan

Huang

Liu

et al. 2018

J Exp Clin Cancer Res

131

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BackgroundInosine 5′-monophosphate dehydrogenase type II (IMPDH2) was originally identified as an oncogene in several human cancers. However, the clinical significance and biological role of IMPDH2 remain poorly understood in colorectal cancer (CRC).MethodsQuantitative real-time polymerase chain reaction (qPCR), western blotting analysis, the Cancer Genome Atlas (TCGA) data mining and immunohistochemistry were employed to examine IMPDH2 expression in CRC cell lines and tissues. A series of in-vivo and in-vitro assays were performed to demonstrate the function of IMPDH2 and its possible mechanisms in CRC.ResultsIMPDH2 was upregulated in CRC cells and tissues at both mRNA and protein level. High IMPDH2 expression was closely associated with T stage, lymph node state, distant metastasis, lymphovascular invasion and clinical stage, and significantly correlated with poor survival of CRC patients. Further study revealed that overexpression of IMPDH2 significantly promoted the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of CRC cells in vitro and accelerated xenograft tumour growth in nude mice. On the contrary, knockdown of IMPDH2 achieved the opposite effect. Gene set enrichment analysis (GSEA) showed that the gene set related to cell cycle was linked to upregulation of IMPDH2 expression. Our study verified that overexpressing IMPDH2 could promote G1/S phase cell cycle transition through activation of PI3K/AKT/mTOR and PI3K/AKT/FOXO1 pathways and facilitate cell invasion, migration and EMT by regulating PI3K/AKT/mTOR pathway.ConclusionsThese results suggest that IMPDH2 plays an important role in the development and progression of human CRC and may serve as a novel prognostic biomarker and therapeutic target for CRC.

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“…Intriguingly, the preclinical molecule Sanglifehrin A (Table 1b) is known to act as a molecular glue linking IMPDH with cyclophilin A (Fig. 5b) 73 , which itself is implicated in viral capsid packaging, even though it itself is not a human "prey" in the viral-human protein interactome. Similarly, direct viral-human interactions with proteins regulated by the mTORC1 pathway, such as LARP1, and FKBP7, which interact with the viral N and Orf8 proteins, led us to inhibitors of mTORC1, even though that kinase itself is not found to directly interact with a viral protein ( Fig.…”

Section: Identification Of Existing Drugs Targeting Sars-cov-2 Human mentioning

confidence: 99%

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Gordon¹,

Jang²,

Bouhaddou³

et al. 2020

Preprint

432

586

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ABSTRACTAn outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.

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IMPDH2 Is an Intracellular Target of the Cyclophilin A and Sanglifehrin A Complex

Cited by 47 publications

References 49 publications

IMP/GTP balance modulates cytoophidium assembly and IMPDH activity

IMP/GTP balance modulates cytoophidium assembly and IMPDH activity

IMPDH2 promotes colorectal cancer progression through activation of the PI3K/AKT/mTOR and PI3K/AKT/FOXO1 signaling pathways

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

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