LY6E mediates an evolutionarily conserved enhancement of virus infection by targeting a late entry step

Mar, Katrina B.; Rinkenberger, Nicholas; Boys, Ian N.; Eitson, Jennifer L.; McDougal, Matthew B.; Richardson, R. Blake; Schoggins, John W.

doi:10.1038/s41467-018-06000-y

Cited by 103 publications

(115 citation statements)

References 70 publications

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“…We validated that YFVΔSK/Nluc gene expression was neutralized by YFV-specific antibodies and was dependent on several known pathways of flavivirus entry, including clathrin-and dynamin-mediated endocytosis (10,30,(65)(66)(67), endosomal acidification (45,(66)(67)(68)(69), E protein-dependent fusion (31), and dependence on LY6E (32,33) and RPLP1 (34).…”

Section: Discussionmentioning

confidence: 77%

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A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating

Ramanathan

Zhang

Douam

et al. 2020

mBio

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While the basic mechanisms of flavivirus entry and fusion are understood, little is known about the postfusion events that precede RNA replication, such as nucleocapsid disassembly. We describe here a sensitive, conditionally replicationdefective yellow fever virus (YFV) entry reporter, YFVΔSK/Nluc, to quantitively monitor the translation of incoming, virus particle-delivered genomes. We validated that YFVΔSK/Nluc gene expression can be neutralized by YFV-specific antisera and requires known flavivirus entry pathways and cellular factors, including clathrin-and dynamin-mediated endocytosis, endosomal acidification, YFV E glycoprotein-mediated fusion, and cellular LY6E and RPLP1 expression. The initial round of YFV translation was shown to require cellular ubiquitylation, consistent with recent findings that dengue virus capsid protein must be ubiquitylated in order for nucleocapsid uncoating to occur. Importantly, translation of incoming YFV genomes also required valosin-containing protein (VCP)/p97, a cellular ATPase that unfolds and extracts ubiquitylated client proteins from large complexes. RNA transfection and washout experiments showed that VCP/p97 functions at a postfusion, pretranslation step in YFV entry. Finally, VCP/p97 activity was required by other flaviviruses in mammalian cells and by YFV in mosquito cells. Together, these data support a critical role for VCP/p97 in the disassembly of incoming flavivirus nucleocapsids during a postfusion step in virus entry. IMPORTANCE Flaviviruses are an important group of RNA viruses that cause significant human disease. The mechanisms by which flavivirus nucleocapsids are disassembled during virus entry remain unclear. Here, we used a yellow fever virus entry reporter, which expresses a sensitive reporter enzyme but does not replicate, to show that nucleocapsid disassembly requires the cellular protein-disaggregating enzyme valosin-containing protein, also known as p97.

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Section: Discussionmentioning

confidence: 77%

“…Furthermore, YFV-mediated Nluc expression was reduced by genetic ablation of LY6E ( Fig. 2H), a host factor that facilitates internalization of flaviviruses and other viruses (32,33), or by RNAi-mediated knockdown of RPLP1 ( Fig. 2I), a ribosomal protein required for efficient flavivirus translation (34).…”

Section: Downloaded Frommentioning

confidence: 99%

A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating

Ramanathan

Zhang

Douam

et al. 2020

mBio

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“…LY6E is ubiquitously expressed in many cell types and functions in modulation of cell signal transduction (41). Recent studies revealed that human LY6E promotes the entry of HIV (46, 47) and multiple enveloped RNA viruses from several viral families (48). Moreover, the enhancement of RNA viral infection is a conserved function of all the mammalian LY6E orthologs examined thus far.…”

Section: Resultsmentioning

confidence: 99%

LY6E Restricts the Entry of Human Coronaviruses, including the currently pandemic SARS-CoV-2

Zhao

Zheng

Chen

et al. 2020

Preprint

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25C3A is a sub-clone of human hepatoblastoma HepG2 cell line with the strong contact inhibition 26 of growth. We fortuitously found that C3A was more susceptible to human coronavirus HCoV-27 OC43 infection than HepG2, which was attributed to the increased efficiency of virus entry into 28 C3A cells. In an effort to search for the host cellular protein(s) mediating the differential 29 susceptibility of the two cell lines to HCoV-OC43 infection, we found that ADAP2, GILT and 30 LY6E, three cellular proteins with known activity of interfering virus entry, expressed at 31 significantly higher levels in HepG2 cells. Functional analyses revealed that ectopic expression 32 of LY6E, but not GILT or ADAP2, in HEK 293 cells inhibited the entry of HCoV-OC43. While 33 overexpression of LY6E in C3A and A549 cells efficiently inhibited the infection of HCoV-34 OC43, knockdown of LY6E expression in HepG2 significantly increased its susceptibility to 35HCoV-OC43 infection. Moreover, we found that LY6E also efficiently restricted the entry 36 mediated by the envelope spike proteins of other human coronaviruses, including the currently 37 pandemic SARS-CoV-2. Interestingly, overexpression of serine protease TMPRSS2 or 38 amphotericin treatment significantly neutralized the IFITM3 restriction of human coronavirus 39 entry, but did not compromise the effect of LY6E on the entry of human coronaviruses. The 40 work reported herein thus demonstrates that LY6E is a critical antiviral immune effector that 41 controls CoV infection and pathogenesis via a distinct mechanism.

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“…To further investigate the role of INPP5E in early HSV1 infection, we separately assessed cell attachment or internalization of virions using two parallel cold-binding assays (Fig. 5F, schema in top panel) that quantified virus particles via qPCR of HSV1 genomic DNA (gDNA) copies 54 . In the attachment assay, 6.8-and 4.3-fold more viral DNA was found associated with the surface-bound fraction in Inpp5e CRISPR#1 and Inpp5e CRISPR#2 vs. Inpp5e +/+ cells, respectively (Fig.…”

Section: Inpp5e Acts As An Antiviral Effector That Modifies Cell Attamentioning

confidence: 99%

Induction of an alternative 5’ leader enhances translation of Inpp5e and resistance to oncolytic virus infection

Hoang

Jia

et al. 2019

Preprint

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Residual cell-intrinsic innate immunity in cancer cells hampers infection with oncolytic viruses. mRNA translation is an important component of innate immunity, yet the targeted cellular mRNAs remain illdefined. We characterized the translatome of resistant murine "4T1" breast cancer cells infected with three of the most clinically advanced oncolytic viruses: Herpes Simplex virus 1, Reovirus and Vaccinia virus. Common among all three infections were translationally derepressed mRNAs involved in ciliary homeostasis including Inpp5e, encoding an inositol 5-phosphatase that modifies lipid second messenger signalling. Translationally repressed in the uninfected condition, viral infection induced expression of an Inpp5e mRNA variant that lacks repressive upstream open reading frames (uORFs) within its 5' leader and is consequently efficiently translated. Furthermore, we show that INPP5E contributes to antiviral immunity by altering virus attachment. These findings uncover a role for translational control through alternative 5' leader expression and assign ciliary proteins such as INPP5E to the cellular antiviral response.

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LY6E mediates an evolutionarily conserved enhancement of virus infection by targeting a late entry step

Cited by 103 publications

References 70 publications

A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating

A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating

LY6E Restricts the Entry of Human Coronaviruses, including the currently pandemic SARS-CoV-2

Induction of an alternative 5’ leader enhances translation of Inpp5e and resistance to oncolytic virus infection

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