Avian reovirus σA-modulated suppression of lactate dehydrogenase and upregulation of glutaminolysis and the mTOC1/eIF4E/HIF-1α pathway to enhance glycolysis and the TCA cycle for virus replication

Chi, Pei-I; Huang, Wei-Ru; Chiu, Hung-Chuan; Li, Jyun-Yi; Nielsen, Brent L.; Liu, Hung-Jen

doi:10.1111/cmi.12946

Cited by 36 publications

(33 citation statements)

References 65 publications

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“…Data were evaluated for statistical significance according to Duncan's multiplerange test (DMRT) using SPSS software (version 20.0). The P values that were less than 0.05 were considered statistically significant (48).…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous Nuclear Ribonucleoprotein A1 and Lamin A/C Modulate Nucleocytoplasmic Shuttling of Avian Reovirus p17

Chiu

Huang

Wang

et al. 2019

J Virol

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Avian reovirus (ARV) p17 protein continuously shuttles between the nucleus and the cytoplasm via transcription-dependent and chromosome region maintenance 1 (CRM1)-independent mechanisms. Nevertheless, whether cellular proteins modulate nucleocytoplasmic shuttling of p17 remains unknown. This is the first report that heterogeneous nuclear ribonucleoprotein (hnRNP) A1 serves as a carrier protein to modulate nucleocytoplasmic shuttling of p17. Both in vitro and in vivo studies indicated that direct interaction of p17 with hnRNP A1 maps within the amino terminus (amino acids [aa] 19 to 40) of p17 and the Gly-rich region of the C terminus of hnRNP A1. Furthermore, our results reveal that the formation of p17-hnRNP A1-transportin 1 carrier-cargo complex is required to modulate p17 nuclear import. Utilizing sequence and mutagenesis analyses, we have identified nuclear export signal (NES) 19 LSLRELAI 26 of p17. Mutations of these residues causes a nuclear retention of p17. In this work, we uncovered that the N-terminal 21 amino acids (aa 19 to 40) of p17 that comprise the NES can modulate both p17 and hnRNP A1 interaction and nucleocytoplasmic shuttling of p17. In this work, the interaction site of p17 with lamin A/C was mapped within the amino terminus (aa 41 to 60) of p17 and p17 colocalized with lamin A/C at the nuclear envelope. Knockdown of hnRNP A1 or lamin A/C led to inhibition of nucleocytoplasmic shuttling of p17 and reduced virus yield. Collectively, the results of this study provide mechanistic insights into hnRNP A1 and lamin A/Cmodulated nucleocytoplasmic shuttling of the ARV p17 protein.IMPORTANCE Avian reoviruses (ARVs) cause considerable economic losses in the poultry industry. The ARV p17 protein continuously shuttles between the nucleus and the cytoplasm to regulate several cellular signaling pathways and interacts with several cellular proteins to cause translation shutoff, cell cycle arrest, and autophagosome formation, all of which enhance virus replication. To date the mechanisms underlying nucleocytoplasmic shuttling of p17 remain largely unknown. Here we report that hnRNP A1 and lamin A/C serve as carrier and mediator proteins to modulate nucleocytoplasmic shuttling of p17. The formation of p17-hnRNP A1-transportin 1 carrier-cargo complex is required to modulate p17 nuclear import. Furthermore, we have identified an NES-containing nucleocytoplasmic shuttling domain (aa 19 to 40) of p17 that is critical for binding to hnRNP A1 and for nucleocytoplasmic shuttling of p17. This study provides novel insights into how hnRNP A1 and lamin A/C modulate nucleocytoplasmic shuttling of the ARV p17 protein. RESULTSCellular proteins hnRNP A1 and lamin A/C coimmunoprecipatate with p17. As shown previously, we identified several cellular proteins, such as nucleoporin Tpr, vimentin, and lamin A/C, that interact with the ARV p17 protein (27,28,30). To explore whether and how cellular proteins are involved in mediating nucleocytoplasmic shut-Chiu et al. FIG 1 p17 interacts with hnRNP A1. (A) Identification of poten...

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Section: Discussionmentioning

confidence: 99%

Heterogeneous Nuclear Ribonucleoprotein A1 and Lamin A/C Modulate Nucleocytoplasmic Shuttling of Avian Reovirus p17

Chiu

Huang

Wang

et al. 2019

J Virol

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“…When nutrients become locally limited, several cancers, including pancreatic, glioblastoma, and ovarian, hijack stromal glutamine synthesis as an alternative supply line to fulfill their increased demands [13][14][15]. Furthermore, glutamine deprivation suppresses expansion of activated T lymphocytes, and competition for nutrients within tissues may affect immune responses to pathological states that exhibit hallmark increases in nutrient consumption (e.g., viral infection, cancer) [10,[16][17][18].…”

Section: Glutaminementioning

confidence: 99%

Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism

2021

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Mitochondria are central organelles that coordinate a vast array of metabolic and biologic functions important for cellular health. Amino acids are intricately linked to the bioenergetic, biosynthetic, and homeostatic function of the mitochondrion and require specific transporters to facilitate their import, export, and exchange across the inner mitochondrial membrane. Here we review key cellular metabolic outputs of eukaryotic mitochondrial amino acid metabolism and discuss both known and unknown transporters involved. Furthermore, we discuss how utilization of compartmentalized amino acid metabolism functions in disease and physiological contexts. We examine how improved methods to study mitochondrial metabolism, define organelle metabolite composition, and visualize cellular gradients allow for a more comprehensive understanding of how transporters facilitate compartmentalized metabolism.

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“…aerobic glycolysis and tumorigenic growth of NPC cells through activation of mTORC1/NF-kappaB signaling [65]. Avian reovirus structural protein sigmaA activates the mTOC1/eIF4E/ HIF-1α pathway to enhance glycolysis and the TCA cycle in the infected cells for virus replication [66]. In this study, we demonstrated that the phosphorylation of AMPK, a kinase that inhibits mTORC1 signaling [37,38], was down-regulated following HHV-6A infection ( S4 Fig), further supporting HHV-6 mediated-mTORC1 activation.…”

Section: Plos Pathogensmentioning

confidence: 99%

Human herpesvirus 6A promotes glycolysis in infected T cells by activation of mTOR signaling

Jia

et al. 2020

PLoS Pathog

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Human herpesvirus 6 (HHV-6) is an important immunosuppressive and immunomodulatory virus worldwide. However, whether and how HHV-6 infection influences the metabolic machinery of the host cell to provide the energy and biosynthetic resources for virus propagation remains unknown. In this study, we identified that HHV-6A infection promotes glucose metabolism in infected T cells, resulting in elevated glycolytic activity with an increase of glucose uptake, glucose consumption and lactate secretion. Furthermore, we explored the mechanisms involved in HHV-6A-mediated glycolytic activation in the infected T cells. We found increased expressions of the key glucose transporters and glycolytic enzymes in HHV-6A-infected T cells. In addition, HHV-6A infection dramatically activated AKT-mTORC1 signaling in the infected T cells and pharmacological inhibition of mTORC1 blocked HHV-6A-mediated glycolytic activation. We also found that direct inhibition of glycolysis by 2-Deoxy-D-glucose (2-DG) or inhibition of mTORC1 activity in HHV-6A-infected T cells effectively reduced HHV-6 DNA replication, protein synthesis and virion production. These results not only reveal the mechanism of how HHV-6 infection affects host cell metabolism, but also suggest that targeting the metabolic pathway could be a new avenue for HHV-6 therapy.

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Avian reovirus σA-modulated suppression of lactate dehydrogenase and upregulation of glutaminolysis and the mTOC1/eIF4E/HIF-1α pathway to enhance glycolysis and the TCA cycle for virus replication

Cited by 36 publications

References 65 publications

Heterogeneous Nuclear Ribonucleoprotein A1 and Lamin A/C Modulate Nucleocytoplasmic Shuttling of Avian Reovirus p17

Heterogeneous Nuclear Ribonucleoprotein A1 and Lamin A/C Modulate Nucleocytoplasmic Shuttling of Avian Reovirus p17

Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism

Human herpesvirus 6A promotes glycolysis in infected T cells by activation of mTOR signaling

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