Phosphatidylinositol 3-Kinase/Akt and MEK/ERK Signaling Pathways Facilitate Sapovirus Trafficking and Late Endosomal Acidification for Viral Uncoating in LLC-PK Cells

Soliman, Mahmoud; Kim, Deok-Song; Park, Jun-Gyu; Kim, Jiyun; Alfajaro, Mia Madel; Baek, Yeong-Bin; Cho, Eun-Hyo; Park, Chul Ho; Kang, Mun-Il; Park, Sang-Ik; Cho, Kyoung-Oh

doi:10.1128/jvi.01674-18

Cited by 8 publications

(6 citation statements)

References 59 publications

(114 reference statements)

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“…The S1PR2 receptor is understudied in the intestine, but some evidence suggests that S1PR2 activation by BAs promotes proliferation (60,61). In LLC-PK1 cells, BAs directly activate signaling pathways (e.g., MEK/ERK cascades) required for PoSaV replication, although whether this requires a specific receptor remains unclear (62). Future studies will determine which signaling cascades are stimulated by BA-activation of S1PR2 in jejunal HIEs and if the activated signaling is required for HuNoV replication and possibly other caliciviruses in their individual model systems.…”

Section: And Ourmentioning

confidence: 99%

Bile acids and ceramide overcome the entry restriction for GII.3 human norovirus replication in human intestinal enteroids

Murakami

Tenge

Karandikar

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

130

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Human noroviruses (HuNoVs) cause sporadic and epidemic outbreaks of gastroenteritis in all age groups worldwide. We previously reported that stem cell-derived human intestinal enteroid (HIE) cultures support replication of multiple HuNoV strains and that some strains (e.g., GII.3) replicate only in the presence of bile. Heat- and trypsin-treatment of bile did not reduce GII.3 replication, indicating a nonproteinaceous component in bile functions as an active factor. Here we show that bile acids (BAs) are critical for GII.3 replication and replication correlates with BA hydrophobicity. Using the highly effective BA, glycochenodeoxycholic acid (GCDCA), we show BAs act during the early stage of infection, BA-dependent replication in HIEs is not mediated by detergent effects or classic farnesoid X receptor or Takeda G protein-coupled receptor 5 signaling but involves another G protein-coupled receptor, sphingosine-1-phosphate receptor 2, and BA treatment of HIEs increases particle uptake. We also demonstrate that GCDCA induces multiple cellular responses that promote GII.3 replication in HIEs, including enhancement of 1) endosomal uptake, 2) endosomal acidification and subsequent activity of endosomal/lysosomal enzyme acid sphingomyelinase (ASM), and 3) ceramide levels on the apical membrane. Inhibitors of endosomal acidification or ASM reduce GII.3 infection and exogenous addition of ceramide alone permits infection. Furthermore, inhibition of lysosomal exocytosis of ASM, which is required for ceramide production at the apical surface, decreases GII.3 infection. Together, our results support a model where GII.3 exploits rapid BA-mediated cellular endolysosomal dynamic changes and cellular ceramide to enter and replicate in jejunal HIEs.

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Section: And Ourmentioning

confidence: 99%

Bile acids and ceramide overcome the entry restriction for GII.3 human norovirus replication in human intestinal enteroids

Murakami

Tenge

Karandikar

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

130

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“…However, a recent study suggested that sapovirus, another non-enveloped virus, activates PI3K-AKT signaling cascade via the PSaV-binding to the cell surface carbohydrate receptors. 31 It is possible that EMCV activates NF-κB with similar mechanisms. TGR5, which is a GPCR receptor for BAs, is located at both the plasma and intracellular organelle membranes.…”

Section: Discussionmentioning

confidence: 99%

Virus-induced accumulation of intracellular bile acids activates the TGR5-β-arrestin-SRC axis to enable innate antiviral immunity

Gao

et al. 2019

Cell Res

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The mechanisms on metabolic regulation of immune responses are still elusive. We show here that viral infection induces immediate-early NF-κB activation independent of viral nucleic acid-triggered signaling, which triggers a rapid transcriptional induction of bile acid (BA) transporter and rate-limiting biosynthesis enzymes as well as accumulation of intracellular BAs in divergent cell types. The accumulated intracellular BAs activate SRC kinase via the TGR5-GRK-β-arrestin axis, which mediates tyrosine phosphorylation of multiple antiviral signaling components including RIG-I, VISA/MAVS, MITA/STING, TBK1 and IRF3. The tyrosine phosphorylation of these components by SRC conditions for efficient innate antiviral immune response. Consistently, TGR5 deficiency impairs innate antiviral immunity, whereas BAs exhibit potent antiviral activity in wild-type but not TGR5-deficient cells and mice. Our findings reveal an intrinsic and universal role of intracellular BA metabolism in innate antiviral immunity.

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“…The direct binding of PKA or AMPK to any of the V-ATPase subunits has not been demonstrated. However, it has been shown that activated pPI3K, pAKT and pERK associate with the E subunit during virus replication [123][124][125]. A quick search through the PhosphoSitePlus database (phosphosite.org), a curated site for phosphorylation and ubiquitylation sites identified by high throughput mass spec analysis, revealed that all of the V-ATPase subunits are modified.…”

Section: V-atpase As a Signalsomementioning

confidence: 99%

The V-ATPase a3 Subunit: Structure, Function and Therapeutic Potential of an Essential Biomolecule in Osteoclastic Bone Resorption

Chu

Zirngibl

Manolson

2021

IJMS

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This review focuses on one of the 16 proteins composing the V-ATPase complex responsible for resorbing bone: the a3 subunit. The rationale for focusing on this biomolecule is that mutations in this one protein account for over 50% of osteopetrosis cases, highlighting its critical role in bone physiology. Despite its essential role in bone remodeling and its involvement in bone diseases, little is known about the way in which this subunit is targeted and regulated within osteoclasts. To this end, this review is broadened to include the three other mammalian paralogues (a1, a2 and a4) and the two yeast orthologs (Vph1p and Stv1p). By examining the literature on all of the paralogues/orthologs of the V-ATPase a subunit, we hope to provide insight into the molecular mechanisms and future research directions specific to a3. This review starts with an overview on bone, highlighting the role of V-ATPases in osteoclastic bone resorption. We then cover V-ATPases in other location/functions, highlighting the roles which the four mammalian a subunit paralogues might play in differential targeting and/or regulation. We review the ways in which the energy of ATP hydrolysis is converted into proton translocation, and go in depth into the diverse role of the a subunit, not only in proton translocation but also in lipid binding, cell signaling and human diseases. Finally, the therapeutic implication of targeting a3 specifically for bone diseases and cancer is discussed, with concluding remarks on future directions.

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Phosphatidylinositol 3-Kinase/Akt and MEK/ERK Signaling Pathways Facilitate Sapovirus Trafficking and Late Endosomal Acidification for Viral Uncoating in LLC-PK Cells

Cited by 8 publications

References 59 publications

Bile acids and ceramide overcome the entry restriction for GII.3 human norovirus replication in human intestinal enteroids

Bile acids and ceramide overcome the entry restriction for GII.3 human norovirus replication in human intestinal enteroids

Virus-induced accumulation of intracellular bile acids activates the TGR5-β-arrestin-SRC axis to enable innate antiviral immunity

The V-ATPase a3 Subunit: Structure, Function and Therapeutic Potential of an Essential Biomolecule in Osteoclastic Bone Resorption

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