Transmissible Gastroenteritis Virus Infection Enhances SGLT1 and GLUT2 Expression to Increase Glucose Uptake

Dai, Lei; Hu, Wei; Lu, Xia; Mao, Xia; Yang, Qian

doi:10.1371/journal.pone.0165585

Cited by 21 publications

(18 citation statements)

References 47 publications

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“…TGEV infection has been shown to increase the level of SGLT protein expression at 48 h, which was consistent with previous reports by Dai Y. Yang, et al Virus Research 280 (2020) 197901 et al (Dai et al, 2016). Moreover, in Fig.…”

Section: Discussionsupporting

confidence: 92%

Decreased NHE3 activity and trafficking in TGEV-infected IPEC-J2 cells via the SGLT1-mediated P38 MAPK/AKt2 pathway

Yang

Song

et al. 2020

Virus Research

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A B S T R A C TTransmissible gastroenteritis virus (TGEV) primarily replicates in intestinal epithelial cells and causes severe damage to host cells, resulting in diarrhea. Surface NHE3 serves as the key regulatory site controlling electroneutral Na + absorption. In this study, our results showed that the surface NHE3 content was significantly reduced following TGEV infection, whereas the total level of protein expression was not significantly changed, and NHE3 activity gradually decreased with prolonged infection time. We then inhibited SGLT1 expression by lentiviral interference and drug inhibition, respectively. Inhibition studies showed that the level of phosphorylation of the downstream key proteins, MAPKAPK-2 and EZRIN, in the SGLT1-mediated p38MAPK/AKt2 signaling pathway was significantly increased. The surface NHE3 expression was also significantly increased, and NHE3 activity was also significantly enhanced. These results demonstrate that a TGEV infection can inhibit NHE3 translocation and attenuates sodium-hydrogen exchange activity via the SGLT1-mediated p38MAPK/AKt2 signaling pathway, affecting cellular electrolyte absorption leading to diarrhea.

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Section: Discussionsupporting

confidence: 92%

Decreased NHE3 activity and trafficking in TGEV-infected IPEC-J2 cells via the SGLT1-mediated P38 MAPK/AKt2 pathway

Yang

Song

et al. 2020

Virus Research

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“…Human cytomegalovirus (HCMV), a herpesvirus, induces the sugar transporter, GLUT4 to increase glucose uptake during infection [ 53 ]. Whereas, transmissible gastroenteritis virus (TGEV), a coronavirus, induces multiple sugar transporters EGFR, SGLT1, and GLUT2 for glucose uptake [ 54 ]. Rhinoviruses (RVs) are responsible for the majority of upper airway infections, and they enhance the expression of the PI3K-regulated glucose transporter GLUT1; glucose deprivation from medium and via glycolysis inhibition by 2-deoxyglucose impairs viral replication [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

The Structure of the Membrane Protein of SARS-CoV-2 Resembles the Sugar Transporter SemiSWEET

Thomas

2020

PAI

134

115

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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the disease COVID-19 that has decimated the health and economy of our planet. The virus causes the disease not only in people but also in companion and wild animals. People with diabetes are at risk of the disease. As yet we do not know why the virus has been highly successful in causing the pandemic within 3 months of its first report. The structural proteins of SARS include membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S). Methods: The structure and function of the most abundant structural protein of SARS-CoV-2, the membrane (M) glycoprotein, is not fully understood. Using in silico analyses we determined the structure and potential function of the M protein. Results: The M protein of SARS-CoV-2 is 98.6% similar to the M protein of bat SARS-CoV, maintains 98.2% homology with pangolin SARS-CoV, and has 90% homology with the M protein of SARS-CoV; whereas, the similarity is only 38% with the M protein of MERS-CoV. In silico analyses showed that the M protein of SARS-CoV-2 has a triple helix bundle, forms a single 3-transmembrane domain, and is homologous to the prokaryotic sugar transport protein SemiSWEET. SemiSWEETs are related to the PQ-loop family whose members function as cargo receptors in vesicle transport, mediate movement of basic amino acids across lysosomal membranes, and are also involved in phospholipase flippase function. Conclusions: The advantage and role of the M protein having a sugar transporter-like structure is not clearly understood. The M protein of SARS-CoV-2 interacts with S, E, and N protein. The S protein of the virus is glycosylated. It could be hypothesized that the sugar transporter-like structure of the M protein influences glycosylation of the S protein. Endocytosis is critical for the internalization and maturation of RNA viruses, including SARS-CoV-2. Sucrose is involved in endosome and lysosome maturation and may also induce autophagy, pathways that help in the entry of the virus. Overall, it could be hypothesized that the SemiSWEET sugar transporter-like structure of the M protein may be involved in multiple functions that may aid in the rapid proliferation, replication, and immune evasion of the SARS-CoV-2 virus. Biological experiments would validate the presence and function of the SemiSWEET sugar transporter.

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“…Research has shown that SGLT1 plays a critical role during the process of TGEV infection in cells. Dai et al (2016) reported that SGLT1 protein levels were upregulated and glucose uptake in the small intestine was enhanced in the early stage of TGEV infection of IPEC-J2 cells. However, later, the glucose intake of the intestinal epithelium decreased ( Dai et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…We next investigated whether TGEV infection regulated the activity, abundance, and mobility of NHE3 through EGFR in IPEC-J2 cells. The spike protein (S) of TGEV combines with EGFR to activate the downstream PI3K signaling pathway, allowing TGEV to invade small intestinal epithelial cells ( Dai et al, 2016 ). Our results showed that the levels of p-EGFR and p-ERK were significantly upregulated in porcine intestinal epithelial cells after TGEV infection.…”

Section: Discussionmentioning

confidence: 99%

EGFR as a Negative Regulatory Protein Adjusts the Activity and Mobility of NHE3 in the Cell Membrane of IPEC-J2 Cells With TGEV Infection

et al. 2018

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Transmissible gastroenteritis (TGE) has caused devastating economic losses to the swine industry worldwide, despite extensive research focusing on the pathogenesis of virus infection. The molecular pathogenic mechanism of TGEV-induced diarrhea in piglets is unknown. Intestinal diarrhea is closely related to the function of the Na+/H+ exchanger protein NHE3 in the brush border membrane of small intestine epithelial cells. The epidermal growth factor receptor (EGFR) may act to regulate NHE3 expression. In addition, EGFR may promote viral invasion of host cells. The present study aimed to determine whether NHE3 activity is regulated by altering EGFR expression to affect Na+ absorption in TGEV-infected intestinal epithelial cells. Porcine intestinal epithelial cells were used as models for TGEV infection. The results showed that Na+ absorption and NHE3 expression levels decreased in TGEV-infected cells. Proliferation of TGEV within IPEC-J2 cells could be inhibited by treatment with the EGFR inhibitor AG1478 and knockdown; resulting in recovery of Na+ absorption in TGEV infected cells and increasing the activity and expression of NHE3. Moreover, we demonstrated that NHE3 activity was regulated through the EGFR/ERK pathway. Importantly, NHE3 mobility on the plasma membrane of TGEV infected cells was significantly weaker than that in normal cells, and EGFR inhibition and knockdown recovered this mobility. Our research indicated that NHE3 activity was negatively regulated by EGFR in TGEV-infected intestinal epithelial cells.

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Transmissible Gastroenteritis Virus Infection Enhances SGLT1 and GLUT2 Expression to Increase Glucose Uptake

Cited by 21 publications

References 47 publications

Decreased NHE3 activity and trafficking in TGEV-infected IPEC-J2 cells via the SGLT1-mediated P38 MAPK/AKt2 pathway

Decreased NHE3 activity and trafficking in TGEV-infected IPEC-J2 cells via the SGLT1-mediated P38 MAPK/AKt2 pathway

The Structure of the Membrane Protein of SARS-CoV-2 Resembles the Sugar Transporter SemiSWEET

EGFR as a Negative Regulatory Protein Adjusts the Activity and Mobility of NHE3 in the Cell Membrane of IPEC-J2 Cells With TGEV Infection

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