Eukaryotic host translation shutoff by virus (kw:KW-1193)

The majority of cellular mRNAs initiatetranslation through the recruitment of a multisubunit translation initiation complex termed eIF4F, which consists of the cap-binding protein eIF4E, the RNA helicase eIF4A, and the adaptor protein eIF4G. eIF4G bindspoly(A)-binding protein (PABP) to mediate 5' -> 3' communication, probably to promote efficient translation of intact correctly processed mRNAs.eIF4E binding protein 1 (eIF4E-BP1) functions as a translational repressor that limits eIF4E availability and therefore eIF4F complex formation.

Viruses have evolved ways of interacting with the host translational machinery toshutoff host gene expression. This global inhibition of cellular protein synthesis serves to ensure maximal viral gene expression and to evade host immune response

.
All the viruses inducing the shutoff of translation are able to continue to translate at least part of their mRNAs using non-canonical translation:IRES,Ribosome shunting, or VPG initiation. For adenoviridae, polyomaviridae and togaviridae the cellular translation shutoff takes place at the late phase of infection and ensures an optimal production of viral structural proteins.
Under stress conditions such as viral infection some cellular translation can continue when the cap-dependent translation initiation is inhibited. Expression of specific cellular proteins seems to occur through cap-independent mechanisms

Viruses inducing host translation shutoff:

Family	Virus	Viral protein	Shutoff strategy	Viral translation	ref.
Adenoviridae	Adenovirus	Shutoff protein 100K	Inhibits eIF4G-Mnk1 and prevents EIF4E phosphorylation	Ribosome shunting on late mRNAs
Bunyaviridae	Bunyamwera virus	Nucleoprotein	Nuclear retention of PABP	Viral mRNAs non polyadenylated
Caliciviridae	Norovirus Feline calicivirus	Protease 3C Protease	PABP cleavage	VPg
	Feline calicivirus	Protease	Cleavage of eIF4G1 and eIF4G2	VPg
Dicistroviridae	Cripavirus	?	Dissociation of eIF4G and eIF4E	IRES
Orthomyxoviridae	Influenza virus	?	Dephosphorylation of of eIF-4E	eIF-4E independent translation of viral mRNAs
Picornaviridae	Poliovirus	Protease 2A	Cleavage of eIF4GI and eIF4GII	IRES
		Protease 3C	Cleavage of eIF5B	IRES
		Protease 3C	PABP cleavage	IRES
	Rhinovirus	Protease 2A	Cleavage of eIF4GI and eIF4GII	IRES
	Coxsackie virus	Protease 2A	Cleavage of eIF4GI and eIF4GII	IRES
	Coxsackie virus	Protease 2A,3C	PABP cleavage	IRES
		Protease 3C	Cleavage of eIF5B	IRES
	Encephalomyocarditis virus	Protein 2A	?	IRES
		?	Dephosphorylation of 4E-BP1	IRES
	Foot-and-mouth disease virus	Leader protease	Cleavage of eIF4GI and eIF4GII	IRES
		Protease 3C	Cleavage of PABP, eIF3a, eIF3b, and eIF4A	IRES
Polyomaviridae	SV40	Small T antigen	Dephosphorylation of 4E-BP1	IRES
Reoviridae	Rotavirus	NSP3	Interacts with EIF4G and evicts PABP from initiation complexes. Nuclear relocalization of PABP	NSP3 replaces PABP andbind the non polyAdenylated viral mRNAs
Rhabdoviridae	Vesicular stomatitis virus	?	Dephosphorylation of 4E-BP1	classical
Retroviridae	HIV-1	Protease	Cleavage of eIF4GI and PABP	IRES
	HTLV-1	Protease	Cleavage of eIF4GI	IRES
	Moloney murine leukemia virus	Protease	Cleavage of eIF4GI and eIF4GII	IRES
Togaviridae	Rubella virus	Capsid protein	PABP sequestration	classical
	Sindbis virus		dsRNA leading to PKR-mediated inhibition of eIF2alpha	DLP
Coronaviridae	SARS-CoV	Nsp1	Binding to host 40S subunit	Viral mRNA protected by 5'-end leader sequence
	Bat-CoV	Nsp1	-	-
	TGEV	Nsp1	-	-

Viral molecular biologyVirion
Virus entry
Virus latency
Transcription and replication
Host-virus interactions
Virus exit

Host cell shutoffTranscription shutoff
»Inhibition of transcription initiation
»Inhibition of RNA polymerase II

mRNA suppression
»Inhibition of pre-mRNA processing
»Inhibition of mRNA nuclear export
»Virus-mediated mRNA decay

Translation shutoff

Viral subversion of the host protein synthesis machinery.
Walsh D, Mohr I.
Nat Rev Microbiol. 2011 Oct 17;9(12):860-75. Review. PubMedPMID: 22002165

Bunyamwera orthobunyavirusS-segment untranslated regions mediate poly(A) tail-independent translation.
Blakqori G, van Knippenberg I, Elliott RM. J
Virol. 2009 Apr;83(8):3637-46. PubMed PMID: 19193790

Modulation of enteroviral proteinase cleavage ofpoly(A)-binding protein (PABP) by conformation and PABP-associated factors.
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Cleavage ofeukaryotic initiation factor eIF5B by enterovirus 3C proteases.
de Breyne S, Bonderoff JM, Chumakov KM, Lloyd RE, Hellen CU.
Virology. 2008Aug 15;378(1):118-22.

Proteolysis of human eukaryotic translation initiation factor eIF4GII, but not eIF4GI, coincides with the shutoff of host protein synthesis after poliovirus infection.
Gradi A, Svitkin YV, Imataka H, Sonenberg N
Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11089-94.

Mapping of functional domains in eukaryotic protein synthesis initiation factor 4G (eIF4G) with picornaviral proteases. Implications for cap-dependent and cap-independent translational initiation.
Lamphear BJ, Kirchweger R, Skern T, Rhoads RE
J Biol Chem. 1995 Sep 15;270(37):21975-83.

Activation of thetranslational suppressor 4E-BP1 following infection with encephalomyocarditisvirus and poliovirus.
Gingras AC, Svitkin Y, Belsham GJ, Pause A, Sonenberg N.
Proc Natl Acad Sci U S A. 1996 May 28;93(11):5578-83.

Phosphorylation state of thecap-binding protein eIF4E during viral infection.
Kleijn M, Vrins CL, Voorma HO, Thomas AA.
Virology. 1996 Mar15;217(2):486-94.

Poly(A) binding protein,C-terminally truncated by the hepatitis A virus proteinase 3C, inhibits viraltranslation.
Zhang B, Morace G, Gauss-M?ller V, Kusov Y.
Nucleic Acids Res. 2007;35(17):5975-84.

Cleavage ofPoly(A)-binding protein by coxsackievirus 2A protease in vitro and in vivo:another mechanism for host protein synthesis shutoff?
Kerekatte V, Keiper BD, Badorff C, Cai A, Knowlton KU, Rhoads RE.
J Virol. 1999Jan;73(1):709-17.

Cleavage ofeukaryotic initiation factor eIF5B by enterovirus 3C proteases.
de Breyne S, Bonderoff JM, Chumakov KM, Lloyd RE, Hellen CU.
Virology. 2008Aug 15;378(1):118-22. Epub 2008 Jun 24.

Cleavage of eukaryotic translation initiation factor 4GII within foot-and-mouth disease virus-infected cells: identification of the L-protease cleavage site in vitro.
Gradi A, Foeger N, Strong R, Svitkin YV, Sonenberg N, Skern T, Belsham GJ
J Virol. 2004 Apr;78(7):3271-8.

Foot-and-mouthdisease virus infection induces proteolytic cleavage of PTB, eIF3a,b, and PABPRNA-binding proteins.
Rodriguez Pulido M, Serrano P, Saiz M, Martinez-Salas E.
Virology. 2007 Aug 1;364(2):466-74.

Calicivirus translation initiation requires aninteraction between VPg and eIF 4 E.
Goodfellow I, Chaudhry Y, Gioldasi I, Gerondopoulos A, Natoni A, Labrie L,Lalibert? JF, Roberts L.
EMBO Rep. 2005 Oct;6(10):968-72.

Calicivirus 3C-like proteinase inhibits cellular translation by cleavage ofpoly(A)-binding protein.
Kuyumcu-Martinez M, Belliot G, Sosnovtsev SV, Chang KO, Green KY, Lloyd RE.
J Virol. 2004 Aug;78(15):8172-82.

Rotavirus RNA-binding protein NSP3interacts with eIF4GI and evicts the poly(A) binding protein from eIF4F.
Piron M, Vende P, Cohen J, Poncet D.
EMBO J.1998 Oct 1;17(19):5811-21.

Nuclear localization of cytoplasmic poly(A)-binding protein uponrotavirus infection involves the interaction of NSP3 with eIF4G and RoXaN.
Harb M, Becker MM, Vitour D, Baron CH, Vende P, Brown SC, Bolte S, Arold ST,Poncet D.
J. Virol. 2008 Nov;82(22):11283-93.

In vitro cleavage of eIF4GI but not eIF4GII by HIV-1 protease and its effects on translation in the rabbit reticulocyte lysate system.
Ohlmann T, Pr?v?t D, D?cimo D, Roux F, Garin J, Morley SJ, Darlix JL
J Mol Biol. 2002 Apr 19;318(1):9-20.

HIV protease cleavespoly(A)-binding protein.
Alvarez E, Castell? A, Men?ndez-Arias L, Carrasco L.
Biochem J. 2006 Jun 1;396(2):219-26.

HIV- 1 protease inhibits Cap- and poly(A)-dependent translation uponeIF4GI and PABP cleavage.
Castell? A, Franco D, Moral-L?pez P, Berlanga JJ, Alvarez E, Wimmer E,Carrasco L.
PLoS One. 2009 Nov 24;4(11):e7997.

The eukaryotic translation initiationfactor 4GI is cleaved by different retroviral proteases.
Alvarez E, Men?ndez-Arias L, Carrasco L.
J Virol. 2003Dec;77(23):12392-400.

Rubella virus capsid proteininteracts with poly(a)-binding protein and inhibits translation.
Ilkow CS, Mancinelli V, Beatch MD, Hobman TC.
J Virol. 2008May;82(9):4284-94.

Translational resistance of late alphavirus mRNA to eIF2alpha phosphorylation: astrategy to overcome the antiviral effect of protein kinase PKR.
Ventoso I, Sanz MA, Molina S, Berlanga JJ, Carrasco L, Esteban M.
Genes Dev. 2006Jan 1;20(1):87-100.

Diversity in viralanti-PKR mechanisms: a remarkable case of evolutionary convergence.
Domingo-Gil E, Toribio R, N?jera JL, Esteban M, Ventoso I.
PLoS One.2011 Feb 2;6(2):e16711.

Rubella virus capsid proteininteracts with poly(a)-binding protein and inhibits translation.
Ilkow CS, Mancinelli V, Beatch MD, Hobman TC.
J Virol. 2008May;82(9):4284-94.

Diversity in viralanti-PKR mechanisms: a remarkable case of evolutionary convergence.
Domingo-Gil E, Toribio R, N?jera JL, Esteban M, Ventoso I.
PLoS One.2011 Feb 2;6(2):e16711.

Vesicular stomatitis virus infection alters the eIF4Ftranslation initiation complex and causes dephosphorylation of the eIF4E bindingprotein 4E-BP1.
Connor JH, Lyles DS.
J Virol. 2002 Oct;76(20):10177-87.

Modification of eukaryotic initiation factor 4Fduring infection by influenza virus.
Feigenblum D, Schneider RJ.
J Virol. 1993 Jun;67(6):3027-35.

Influenza virus polymeraseconfers independence of the cellular cap-binding factor eIF4E for viral mRNAtranslation.
Y?ng?ez E, Rodriguez P, Goodfellow I, Nieto A.
Virology. 2012 Jan 20;422(2):297-307.

Effects of simian virus 40 large and smalltumor antigens on mammalian target of rapamycin signaling: small tumor antigenmediates hypophosphorylation of eIF4E-binding protein 1 late in infection.
Yu Y, Kudchodkar SB, Alwine JC.
JVirol. 2005 Jun;79(11):6882-9.

19S late mRNAs of simian virus 40 have an internal ribosomeentry site upstream of the virion structural protein 3 coding sequence.
Yu Y, Alwine JC.
J Virol.2006 Jul;80(13):6553-8.

Structural basis for competitive inhibition ofeIF4G-Mnk1 interaction by the adenovirus 100-kilodalton protein.
Cuesta R, Xi Q, Schneider RJ.
J Virol. 2004Jul;78(14):7707-16.

Manipulation of the host translation initiation complex eIF4F by DNAviruses.
Walsh D.
Biochem Soc Trans. 2010 Dec;38(6):1511-6. Review.

Severe acute respiratory syndrome coronavirus protein nsp1 is a novel eukaryotic translation inhibitor that represses multiple steps of translation initiation.
Lokugamage KG, Narayanan K, Huang C, Makino S
J Virol. 2012 Dec;86(24):13598-608.

Suppression of host gene expression by nsp1 proteins of group 2 bat coronaviruses.
Tohya Y, Narayanan K, Kamitani W, Huang C, Lokugamage K, Makino S
J Virol. 2009 May;83(10):5282-8.

Alphacoronavirus transmissible gastroenteritis virus nsp1 protein suppresses protein translation in mammalian cells and in cell-free HeLa cell extracts but not in rabbit reticulocyte lysate.
Huang C, Lokugamage KG, Rozovics JM, Narayanan K, Semler BL, Makino S
J Virol. 2011 Jan;85(1):638-43.

Mutational analysis of the EMCV 2A protein identifies a nuclear localization signal and an eIF4E binding site.
Groppo R, Brown BA, Palmenberg AC
Virology. 2011 Feb 5;410(1):257-67.

L protease from foot and mouth disease virus confers eIF2-independent translation for mRNAs bearing picornavirus IRES
Pablo Moral-L?pez, Enrique Alvarez, Natalia Redondo, Tim Skern, Luis Carrasco
FEBS Lett. November 3, 2014; 588: 4053-4059

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Eukaryotic host translation shutoff by virus (kw:KW-1193)

Viruses inducing host translation shutoff:

Matching UniProtKB/Swiss-Prot entries

Nucleoprotein (Nucleocapsid protein) (Protein N)

Protein OPG173

Gag-Pol polyprotein (Pr160Gag-Pol)

Genome polyprotein

Gag-Pro polyprotein (Pr76Gag-Pro)

Replicase polyprotein 1a (pp1a) (ORF1a polyprotein)

Replicase polyprotein 1ab (pp1ab) (ORF1ab polyprotein)

Shutoff protein (100 kDa protein) (p100K) (100K-chaperone protein) (L4-100K) (Shutoff protein 100K)

Small t antigen (ST) (ST-AG)

Host translation inhibitor E66L (pE66L)