ID TRS1_HCMVA Reviewed; 788 AA.
AC P09695; Q7M6U0;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1989, sequence version 1.
DT 27-MAR-2024, entry version 84.
DE RecName: Full=Protein HHLF1;
GN Name=TRS1;
OS Human cytomegalovirus (strain AD169) (HHV-5) (Human herpesvirus 5).
OC Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes;
OC Herpesvirales; Orthoherpesviridae; Betaherpesvirinae; Cytomegalovirus;
OC Cytomegalovirus humanbeta5; Human cytomegalovirus.
OX NCBI_TaxID=10360;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3031311; DOI=10.1016/0022-2836(86)90359-1;
RA Weston K.M., Barrell B.G.;
RT "Sequence of the short unique region, short repeats, and part of the long
RT repeats of human cytomegalovirus.";
RL J. Mol. Biol. 192:177-208(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=2161319; DOI=10.1007/978-3-642-74980-3_6;
RA Chee M.S., Bankier A.T., Beck S., Bohni R., Brown C.M., Cerny R.,
RA Horsnell T., Hutchison C.A. III, Kouzarides T., Martignetti J.A.,
RA Preddie E., Satchwell S.C., Tomlinson P., Weston K.M., Barrell B.G.;
RT "Analysis of the protein-coding content of the sequence of human
RT cytomegalovirus strain AD169.";
RL Curr. Top. Microbiol. Immunol. 154:125-169(1990).
RN [3]
RP GENOME REANNOTATION.
RX PubMed=12533697; DOI=10.1099/vir.0.18606-0;
RA Davison A.J., Dolan A., Akter P., Addison C., Dargan D.J., Alcendor D.J.,
RA McGeoch D.J., Hayward G.S.;
RT "The human cytomegalovirus genome revisited: comparison with the chimpanzee
RT cytomegalovirus genome.";
RL J. Gen. Virol. 84:17-28(2003).
RN [4]
RP ERRATUM OF PUBMED:12533697.
RA Davison A.J., Dolan A., Akter P., Addison C., Dargan D.J., Alcendor D.J.,
RA McGeoch D.J., Hayward G.S.;
RL J. Gen. Virol. 84:1053-1053(2003).
RN [5]
RP SUBCELLULAR LOCATION.
RX PubMed=8995674; DOI=10.1128/jvi.71.2.1485-1496.1997;
RA Romanowski M.J., Shenk T.;
RT "Characterization of the human cytomegalovirus irs1 and trs1 genes: a
RT second immediate-early transcription unit within irs1 whose product
RT antagonizes transcriptional activation.";
RL J. Virol. 71:1485-1496(1997).
RN [6]
RP IDENTIFICATION.
RX PubMed=15452216; DOI=10.1128/jvi.78.20.10960-10966.2004;
RA Varnum S.M., Streblow D.N., Monroe M.E., Smith P., Auberry K.J.,
RA Pasa-Tolic L., Wang D., Camp D.G. II, Rodland K., Wiley S., Britt W.,
RA Shenk T., Smith R.D., Nelson J.A.;
RT "Identification of proteins in human cytomegalovirus (HCMV) particles: the
RT HCMV proteome.";
RL J. Virol. 78:10960-10966(2004).
RN [7]
RP ERRATUM OF PUBMED:15452216.
RA Varnum S.M., Streblow D.N., Monroe M.E., Smith P., Auberry K.J.,
RA Pasa-Tolic L., Wang D., Camp D.G. II, Rodland K., Wiley S., Britt W.,
RA Shenk T., Smith R.D., Nelson J.A.;
RL J. Virol. 78:13395-13395(2004).
RN [8]
RP RNA-BINDING, AND DOMAIN.
RC STRAIN=Toledo;
RX PubMed=15919885; DOI=10.1128/jvi.79.12.7311-7318.2005;
RA Hakki M., Geballe A.P.;
RT "Double-stranded RNA binding by human cytomegalovirus pTRS1.";
RL J. Virol. 79:7311-7318(2005).
RN [9]
RP FUNCTION, INTERACTION WITH HOST EIF2AK2, AND DOMAIN.
RC STRAIN=rTowne-1;
RX PubMed=16987971; DOI=10.1128/jvi.00957-06;
RA Hakki M., Marshall E.E., De Niro K.L., Geballe A.P.;
RT "Binding and nuclear relocalization of protein kinase R by human
RT cytomegalovirus TRS1.";
RL J. Virol. 80:11817-11826(2006).
RN [10]
RP INTERACTION WITH HOST HSPA5.
RC STRAIN=Towne;
RX PubMed=19741001; DOI=10.1128/jvi.00762-09;
RA Buchkovich N.J., Maguire T.G., Paton A.W., Paton J.C., Alwine J.C.;
RT "The endoplasmic reticulum chaperone BiP/GRP78 is important in the
RT structure and function of the human cytomegalovirus assembly compartment.";
RL J. Virol. 83:11421-11428(2009).
RN [11]
RP INTERACTION WITH UL44.
RX PubMed=20444996; DOI=10.1099/vir.0.022640-0;
RA Strang B.L., Geballe A.P., Coen D.M.;
RT "Association of human cytomegalovirus proteins IRS1 and TRS1 with the viral
RT DNA polymerase accessory subunit UL44.";
RL J. Gen. Virol. 91:2167-2175(2010).
RN [12]
RP FUNCTION, AND INTERACTION WITH HOST BECN1.
RX PubMed=22205736; DOI=10.1128/jvi.05746-11;
RA Chaumorcel M., Lussignol M., Mouna L., Cavignac Y., Fahie K.,
RA Cotte-Laffitte J., Geballe A., Brune W., Beau I., Codogno P., Esclatine A.;
RT "The human cytomegalovirus protein TRS1 inhibits autophagy via its
RT interaction with Beclin 1.";
RL J. Virol. 86:2571-2584(2012).
RN [13]
RP RNA-BINDING, AND MUTAGENESIS OF ARG-122; ARG-125; LYS-126; ARG-130;
RP ARG-151; ARG-163; ARG-231; GLY-242 AND ARG-246.
RX PubMed=23601785; DOI=10.1016/j.virol.2013.03.024;
RA Bierle C.J., Semmens K.M., Geballe A.P.;
RT "Double-stranded RNA binding by the human cytomegalovirus PKR antagonist
RT TRS1.";
RL Virology 442:28-37(2013).
RN [14]
RP FUNCTION, AND DOMAIN.
RX PubMed=26819306; DOI=10.1128/jvi.02714-15;
RA Ziehr B., Vincent H.A., Moorman N.J.;
RT "Human Cytomegalovirus pTRS1 and pIRS1 Antagonize Protein Kinase R To
RT Facilitate Virus Replication.";
RL J. Virol. 90:3839-3848(2016).
CC -!- FUNCTION: Inhibits the establishment of the antiviral state and the
CC integrated stress response (ISR) in the infected cell. Prevents the
CC phosphorylation of the host eukaryotic translation initiation factor
CC eIF-2alpha/EIF2S1 and thus the shutoff of viral and cellular protein
CC synthesis by directly interacting with EIF2AK2/PKR (PubMed:16987971,
CC PubMed:26819306). Prevents stress granule formation in response to eIF-
CC 2alpha/EIF2S1 phosphorylation, thereby rescuing viral replication and
CC protein synthesis (PubMed:26819306). Also inhibits host autophagy by
CC interacting with host Beclin-1/BECN1 (PubMed:22205736).
CC {ECO:0000269|PubMed:16987971, ECO:0000269|PubMed:22205736,
CC ECO:0000269|PubMed:26819306}.
CC -!- SUBUNIT: Interacts with host EIF2AK2/PKR; this interaction retains
CC EIF2AK2 to the host nucleus and prevents its activation
CC (PubMed:16987971). Interaction (via N-terminus) with host BECN1; this
CC interaction inhibits host autophagy (PubMed:20444996, PubMed:22205736).
CC Interacts with the viral DNA polymerase accessory subunit UL44
CC (PubMed:20444996). Interacts with host HSPA5 (PubMed:19741001).
CC {ECO:0000269|PubMed:16987971, ECO:0000269|PubMed:19741001,
CC ECO:0000269|PubMed:20444996, ECO:0000269|PubMed:22205736}.
CC -!- SUBCELLULAR LOCATION: Virion {ECO:0000269|PubMed:8995674}. Host
CC cytoplasm {ECO:0000269|PubMed:8995674}. Host nucleus
CC {ECO:0000269|PubMed:8995674}.
CC -!- DOMAIN: The N-terminus binds RNA (PubMed:15919885). The C-terminus is
CC required to bind and antagonize host EIF2AK2/PKR (PubMed:16987971,
CC PubMed:26819306). {ECO:0000269|PubMed:15919885,
CC ECO:0000269|PubMed:16987971, ECO:0000269|PubMed:26819306}.
CC -!- SIMILARITY: Belongs to the herpesviridae US22 family. {ECO:0000305}.
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DR EMBL; X17403; CAA35269.1; -; Genomic_DNA.
DR EMBL; X04650; CAB37121.1; -; Genomic_DNA.
DR EMBL; BK000394; DAA00094.1; -; Genomic_DNA.
DR PIR; C27349; QQBEE3.
DR Proteomes; UP000008991; Genome.
DR Proteomes; UP000008992; Genome.
DR GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0044423; C:virion component; IEA:UniProtKB-KW.
DR GO; GO:0030291; F:protein serine/threonine kinase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0039521; P:suppression by virus of host autophagy; IEA:UniProtKB-KW.
DR GO; GO:0039580; P:suppression by virus of host PKR signaling; IEA:UniProtKB-KW.
DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW.
DR InterPro; IPR003360; US22-like.
DR Pfam; PF02393; US22; 2.
PE 1: Evidence at protein level;
KW Host cytoplasm; Host nucleus; Host-virus interaction;
KW Inhibition of host autophagy by virus;
KW Inhibition of host innate immune response by virus;
KW Inhibition of host interferon signaling pathway by virus;
KW Inhibition of host PKR by virus; Interferon antiviral system evasion;
KW Reference proteome; Viral immunoevasion; Virion.
FT CHAIN 1..788
FT /note="Protein HHLF1"
FT /id="PRO_0000115266"
FT REGION 1..82
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 74..248
FT /note="RNA-binding"
FT /evidence="ECO:0000269|PubMed:15919885"
FT REGION 366..385
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 609..663
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 671..788
FT /note="Interaction with host EIF2AK2/PKR"
FT /evidence="ECO:0000269|PubMed:26819306"
FT COMPBIAS 26..52
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 609..633
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 648..663
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MUTAGEN 122
FT /note="R->A: 25% loss of viral replication."
FT /evidence="ECO:0000269|PubMed:23601785"
FT MUTAGEN 125
FT /note="R->A: 35% loss of viral replication."
FT /evidence="ECO:0000269|PubMed:23601785"
FT MUTAGEN 126
FT /note="K->A: 25% loss of viral replication."
FT /evidence="ECO:0000269|PubMed:23601785"
FT MUTAGEN 130
FT /note="R->A: 25% loss of viral replication."
FT /evidence="ECO:0000269|PubMed:23601785"
FT MUTAGEN 151
FT /note="R->A: 75% loss of viral replication. Complete loss
FT of dsRNA binding."
FT /evidence="ECO:0000269|PubMed:23601785"
FT MUTAGEN 163
FT /note="R->A: 15% loss of viral replication."
FT /evidence="ECO:0000269|PubMed:23601785"
FT MUTAGEN 231
FT /note="R->A: 10% loss of viral replication."
FT /evidence="ECO:0000269|PubMed:23601785"
FT MUTAGEN 242
FT /note="G->A: 90% loss of viral replication. Complete loss
FT of dsRNA binding."
FT /evidence="ECO:0000269|PubMed:23601785"
FT MUTAGEN 246
FT /note="R->A: 25% loss of viral replication."
FT /evidence="ECO:0000269|PubMed:23601785"
SQ SEQUENCE 788 AA; 83982 MW; 604BC69C4472BC7A CRC64;
MAQRNGMSPR PPPLGRGRGA GGPSGVGSSP PSSCVPMGAP STAGTGASAA ATTTPGHGVH
RVEPRGPPGA PPSSGNNSNF WHGPERLLLS QIPVERQALT ELEYQAMGAV WRAAFLANST
GRAMRKWSQR DAGTLLPLGR PYGFYARVTP RSQMNGVGAT DLRQLSPRDA WIVLVATVVH
EVDPAADPTL GDKAGHPEGL CAQDGLYLAL GAGFRVFVYD LANNTLILAA RDADEWFRHG
AGEVVRLYRC NRLGVGTPRA TLLPQPALRQ TLLRAEEATA LGRELRRRWA GTTVALQTPG
RRLQPMVLLG AWQELAQYEP FASAPHPASL LTAVRRHLNQ RLCCGWLALG AVLPARWLGC
AAGPATGTAA GTTSPPAASG TETEAAGGDA PCAIAGAVGS AVPVPPQPYG AAGGGAICVP
NADAHAVVGA DAAAAAAPTV MVGSTAMAGP AASGTVPRAM LVVLLDELGA VFGYCPLDGH
VYPLAAELSH FLRAGVLGAL ALGRESAPAA EAARRLLPEL DREQWERPRW DALHLHPRAA
LWAREPHGQL AFLLRPGRGE AEVLTLATKH PAICANVEDY LQDARRRADA QALGLDLATV
VMEAGGQMIH KKTKKPKGKE DESLMKGKHS RYTRPTEPPL TPQASLGRAL RRDDEDWKPS
RLPGEDSWYD LDETFWVLGS NRKNDVYQRR WKKTVLRCGL EIDRPMPTVP KGCRPQTFTH
EGIQLMGGAT QEPLDTGLYA PSHVTSAFVP SVYMPPTVPY PDPAARLCRD MRRVTFSNIA
THYHYNAQ
//
