Dysregulated metabolism underpins Zika-virus-infection-associated impairment in fetal development

Yau, Clement; Low, John Z.H.; Gan, Esther S.; Kwek, Swee Sen; Liang, Cui; Tan, Hwee Cheng; Mok, Darren Z L; Chan, Chee-Yong; Sessions, October M.; Watanabe, Sumio; Vasudevan, Subhash G.; Lee, Yie Hou; Chan, Kap Luk; Ooi, Eng Eong

doi:10.1016/j.celrep.2021.110118

Cited by 25 publications

(23 citation statements)

References 51 publications

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“…Recently, ZBP1/RIPK1/RIPK3 was shown to induce a subset of ISGs in cortical neurons during ZIKA virus infection (Daniels et al, 2019). ZIKA virus induces mitochondrial damage (Ledur et al, 2020;Yau et al, 2021), and the closely related Dengue flavivirus can trigger mtDNA release and promote cGAS-STING signaling (Aguirre et al, 2017;Sun et al, 2017). Therefore, it is possible that RIPK1 and/or RIPK3 participate in the ZBP1-cGAS complex and help sustain IFN-I signaling and ISG expression downstream of mitochondrial stress.…”

Section: Discussionmentioning

confidence: 99%

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

Lei

VanPortfliet

Chen

et al. 2022

Preprint

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Mitochondrial DNA (mtDNA) is a potent agonist of the cyclic GMP-AMP (cGAMP) synthase (cGAS)-Stimulator of Interferon Genes (STING)-type I interferon (IFN-I) pathway. However, the kinetics of mtDNA detection by cGAS or other nucleic acid sensors and the exact immunostimulatory features of mtDNA remain poorly defined. Here, we show that robust and sustained IFN-I responses downstream of mtDNA stress require the nucleic acid sensor Z-DNA binding protein 1 (ZBP1) in a cell death independent manner. Cells experiencing persistent mtDNA release display robust ZBP1 expression, as well as a marked increase in the cytoplasmic pool of cGAS. Biochemical and microscopy analyses reveal that the receptor-interacting protein homotypic interaction motif (RHIMs) of ZBP1 bind the N-terminus of cGAS, leading to its entrapment in the cytoplasm. Moreover, we show that genetic and pharmacologic induction of mtDNA stress leads to the mitochondrial and cytoplasmic accumulation of Z-form DNA. Nuclease treatment or deletion of Z-DNA binding domains of ZBP1 reduces its interaction with cGAS and impairs cGAMP production downstream of mtDNA stress. Finally, we uncover that ZBP1 is a novel regulator of IFN-I-mediated disease pathology, working in tandem with the cGAS-STING pathway to sense mtDNA instability and sustain IFN-I signaling that contributes to cardiac remodeling and heart failure. These results provide new insight into the molecular mechanisms of mtDNA sensing by the innate immune system and reveal that ZBP1 is a cooperative partner for cGAS. Moreover, our findings highlight ZBP1 as a potential therapeutic target in heart failure and other disorders where mtDNA instability drives disease-promoting IFN-I and inflammatory responses.

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Section: Discussionmentioning

confidence: 99%

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

Lei

VanPortfliet

Chen

et al. 2022

Preprint

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“…ZIKV infection elicits a glycolytic response, as shown by increased extracellular acidification rate and expression of key glycolytic genes ( GLUT1 , HK2 , TPI , and MCT4 ), according to bioinformation studies ( Tiwari et al, 2017 ; Singh et al, 2020 ). Furthermore, infection with ZIKV leads to metabolic reprogramming and diversion of glycolytic carbon to PPP ( Yau et al, 2021 ). Therefore, it suggest that ZIKV may increase the flow of PPP by upregulating enzymes including G6PD.…”

Section: Role Of G6pd In Non-neoplastic Diseasesmentioning

confidence: 99%

Recent findings in the regulation of G6PD and its role in diseases

et al. 2022

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Glucose-6-phosphate dehydrogenase (G6PD) is the only rate-limiting enzyme in the pentose phosphate pathway (PPP). Rapidly proliferating cells require metabolites from PPP to synthesize ribonucleotides and maintain intracellular redox homeostasis. G6PD expression can be abnormally elevated in a variety of cancers. In addition, G6PD may act as a regulator of viral replication and vascular smooth muscle function. Therefore, G6PD-mediated activation of PPP may promote tumor and non-neoplastic disease progression. Recently, studies have identified post-translational modifications (PTMs) as an important mechanism for regulating G6PD function. Here, we provide a comprehensive review of various PTMs (e.g., phosphorylation, acetylation, glycosylation, ubiquitination, and glutarylation), which are identified in the regulation of G6PD structure, expression and enzymatic activity. In addition, we review signaling pathways that regulate G6PD and evaluate the role of oncogenic signals that lead to the reprogramming of PPP in tumor and non-neoplastic diseases as well as summarize the inhibitors that target G6PD.

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“…ZIKV specific human targets are mainly involved in mitochondrial translation. Recent studies show that ZIKV infection impairs mitochondrial functions ( Yang et al, 2020 ; Yau et al, 2021 ). On the other hand, SFV specific interactors are involved in non-sense mediated mRNA decay (NMD) ( Contu et al, 2021 ).…”

Section: Viral-host Interactomes Of the Emerging Viruses: Commonaliti...mentioning

confidence: 99%

The Intricacy of the Viral-Human Protein Interaction Networks: Resources, Data, and Analyses

et al. 2022

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Viral infections are one of the major causes of human diseases that cause yearly millions of deaths and seriously threaten global health, as we have experienced with the COVID-19 pandemic. Numerous approaches have been adopted to understand viral diseases and develop pharmacological treatments. Among them, the study of virus-host protein-protein interactions is a powerful strategy to comprehend the molecular mechanisms employed by the virus to infect the host cells and to interact with their components. Experimental protein-protein interactions described in the scientific literature have been systematically captured into several molecular interaction databases. These data are organized in structured formats and can be easily downloaded by users to perform further bioinformatic and network studies. Network analysis of available virus-host interactomes allow us to understand how the host interactome is perturbed upon viral infection and what are the key host proteins targeted by the virus and the main cellular pathways that are subverted. In this review, we give an overview of publicly available viral-human protein-protein interactions resources and the community standards, curation rules and adopted ontologies. A description of the main virus-human interactome available is provided, together with the main network analyses that have been performed. We finally discuss the main limitations and future challenges to assess the quality and reliability of protein-protein interaction datasets and resources.

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Dysregulated metabolism underpins Zika-virus-infection-associated impairment in fetal development

Cited by 25 publications

References 51 publications

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

Recent findings in the regulation of G6PD and its role in diseases

The Intricacy of the Viral-Human Protein Interaction Networks: Resources, Data, and Analyses

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