ID ICP34_HHV11 Reviewed; 248 AA. AC P36313; O12396; DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot. DT 26-FEB-2008, sequence version 2. DT 27-MAR-2024, entry version 89. DE RecName: Full=Neurovirulence factor ICP34.5; DE AltName: Full=Infected cell protein 34.5; DE AltName: Full=protein gamma(1)34.5; GN Name=ICP34.5; Synonyms=RL1; OS Human herpesvirus 1 (strain 17) (HHV-1) (Human herpes simplex virus 1). OC Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes; OC Herpesvirales; Orthoherpesviridae; Alphaherpesvirinae; Simplexvirus; OC Simplexvirus humanalpha1; Human herpesvirus 1. OX NCBI_TaxID=10299; OH NCBI_TaxID=9606; Homo sapiens (Human). RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2839594; DOI=10.1099/0022-1317-69-7-1531; RA McGeoch D.J., Dalrymple M.A., Davison A.J., Dolan A., Frame M.C., McNab D., RA Perry L.J., Scott J.E., Taylor P.; RT "The complete DNA sequence of the long unique region in the genome of RT herpes simplex virus type 1."; RL J. Gen. Virol. 69:1531-1574(1988). RN [2] RP SEQUENCE REVISION. RX PubMed=1321882; DOI=10.1099/0022-1317-73-4-971; RA Dolan A., McKie E., MacLean A.R., McGeoch D.J.; RT "Status of the ICP34.5 gene in herpes simplex virus type 1 strain 17."; RL J. Gen. Virol. 73:971-973(1992). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2846760; DOI=10.1099/0022-1317-69-11-2831; RA Perry L.J., McGeoch D.J.; RT "The DNA sequences of the long repeat region and adjoining parts of the RT long unique region in the genome of herpes simplex virus type 1."; RL J. Gen. Virol. 69:2831-2846(1988). RN [4] RP FUNCTION. RC STRAIN=17syn+, and 17termA; RX PubMed=8077935; DOI=10.1099/0022-1317-75-9-2367; RA Brown S.M., Harland J., MacLean A.R., Podlech J., Clements J.B.; RT "Cell type and cell state determine differential in vitro growth of non- RT neurovirulent ICP34.5-negative herpes simplex virus types 1 and 2."; RL J. Gen. Virol. 75:2367-2377(1994). RN [5] RP FUNCTION. RX PubMed=7996163; DOI=10.1099/0022-1317-75-12-3679; RA Brown S.M., MacLean A.R., Aitken J.D., Harland J.; RT "ICP34.5 influences herpes simplex virus type 1 maturation and egress from RT infected cells in vitro."; RL J. Gen. Virol. 75:3679-3686(1994). RN [6] RP INTERACTION WITH PCNA. RX PubMed=9371605; DOI=10.1128/jvi.71.12.9442-9449.1997; RA Brown S.M., MacLean A.R., McKie E.A., Harland J.; RT "The herpes simplex virus virulence factor ICP34.5 and the cellular protein RT MyD116 complex with proliferating cell nuclear antigen through the 63- RT amino-acid domain conserved in ICP34.5, MyD116, and GADD34."; RL J. Virol. 71:9442-9449(1997). RN [7] RP FUNCTION, AND INTERACTION WITH HOST BECN1. RX PubMed=18005679; DOI=10.1016/j.chom.2006.12.001; RA Orvedahl A., Alexander D., Talloczy Z., Sun Q., Wei Y., Zhang W., Burns D., RA Leib D.A., Levine B.; RT "HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy RT protein."; RL Cell Host Microbe 1:23-35(2007). RN [8] RP INTERACTION WITH HOST C1QBP, AND FUNCTION. RX PubMed=25355318; DOI=10.1074/jbc.m114.603845; RA Wang Y., Yang Y., Wu S., Pan S., Zhou C., Ma Y., Ru Y., Dong S., He B., RA Zhang C., Cao Y.; RT "p32 is a novel target for viral protein ICP34.5 of herpes simplex virus RT type 1 and facilitates viral nuclear egress."; RL J. Biol. Chem. 289:35795-35805(2014). RN [9] RP FUNCTION, INTERACTION WITH HOST UL31, INTERACTION WITH HOST C1QBP, AND RP INTERACTION WITH HOST PRKCA. RX PubMed=27630226; DOI=10.1128/jvi.01392-16; RA Wu S., Pan S., Zhang L., Baines J., Roller R., Ames J., Yang M., Wang J., RA Chen D., Liu Y., Zhang C., Cao Y., He B.; RT "Herpes Simplex Virus 1 Induces Phosphorylation and Reorganization of Lamin RT A/C through the gamma134.5 Protein That Facilitates Nuclear Egress."; RL J. Virol. 90:10414-10422(2016). RN [10] RP FUNCTION, INTERACTION WITH HOST BECN1, INTERACTION WITH HOST C1QBP, RP INTERACTION WITH HOST PPP1CA, AND INTERACTION WITH HOST EIF2AK2/PKR. RX PubMed=28904192; DOI=10.1128/jvi.01156-17; RA Manivanh R., Mehrbach J., Knipe D.M., Leib D.A.; RT "Role of Herpes Simplex Virus 1 gamma34.5 in the Regulation of IRF3 RT Signaling."; RL J. Virol. 91:0-0(2017). RN [11] RP FUNCTION, AND INTERACTION WITH HOST STING/TMEM173. RX PubMed=30045990; DOI=10.1128/jvi.01015-18; RA Pan S., Liu X., Ma Y., Cao Y., He B.; RT "34.5 Protein Inhibits STING Activation That Restricts Viral Replication."; RL J. Virol. 0:0-0(2018). CC -!- FUNCTION: Inhibits the establishment of the immune response and of the CC integrated stress response (ISR) in the infected cell (By similarity). CC Plays essential roles in viral nuclear egress to mediate capsid transit CC across the nuclear membrane (PubMed:25355318). Facilitates nuclear CC egress cooperatively with host C1QBP and protein kinase C/PKC to induce CC lamin A/C phosphorylation and subsequent reorganization CC (PubMed:27630226, PubMed:25355318). In turn, lamina disassembles and CC nuclear egress occurs (PubMed:27630226). Recruits the serine/threonine CC protein phosphatase PPP1CA/PP1-alpha to dephosphorylate the translation CC initiation factor EIF2S1/eIF-2alpha, thereby couteracting the host CC shutoff of protein synthesis involving double-stranded RNA-dependent CC protein kinase EIF2AK2/PKR (By similarity). In turn, controls host IRF3 CC activation and subsequently inhibits host interferon response CC (PubMed:28904192). Controls the DNA sensing pathway by interacting with CC and inhibiting host STING/TMEM173 (PubMed:30045990). Also down- CC modulates the host MHC class II proteins cell surface expression (By CC similarity). Acts as a neurovirulence factor that has a profound effect CC on the growth of the virus in central nervous system tissue, by CC interacting with host BECN1 and thereby antagonizing the host autophagy CC response (PubMed:18005679). {ECO:0000250|UniProtKB:P08353, CC ECO:0000269|PubMed:18005679, ECO:0000269|PubMed:25355318, CC ECO:0000269|PubMed:27630226, ECO:0000269|PubMed:28904192, CC ECO:0000269|PubMed:30045990, ECO:0000269|PubMed:7996163, CC ECO:0000269|PubMed:8077935}. CC -!- SUBUNIT: Interacts with host PPP1CA; this interaction forms a high- CC molecular-weight complex that dephosphorylates EIF2S1/eIF-2alpha (By CC similarity). Interacts with host EIF2S1/eIF-2alpha; this interaction is CC crucial for the specific dephosphorylation of EIF2S1/eIF-2alpha by CC PPP1CA (PubMed:28904192). Binds to proliferating cell nuclear antigen CC (PCNA), which may release host cells from growth arrest and facilitate CC viral replication (PubMed:9371605). Interacts (via N-terminus) with CC host C1QBP; this interaction allows C1QBP to be recruited to the inner CC nuclear membrane by ICP34.5 (PubMed:28904192, PubMed:27630226, CC PubMed:25355318). Interacts with host PRKCA (PubMed:27630226). CC Interacts with protein UL31 (PubMed:27630226). Interacts with host CC STING/TMEM173; this interaction inhibits the intracellular DNA sensing CC pathway (PubMed:30045990). Interacts with host BECN1; this interaction CC modulates host autophagy (PubMed:28904192, PubMed:18005679). CC {ECO:0000250|UniProtKB:P08353, ECO:0000269|PubMed:18005679, CC ECO:0000269|PubMed:25355318, ECO:0000269|PubMed:27630226, CC ECO:0000269|PubMed:28904192, ECO:0000269|PubMed:30045990, CC ECO:0000269|PubMed:9371605}. CC -!- INTERACTION: CC P36313; P62136: PPP1CA; Xeno; NbExp=4; IntAct=EBI-6149234, EBI-357253; CC -!- SUBCELLULAR LOCATION: Host cytoplasm {ECO:0000250|UniProtKB:P08353}. CC Host nucleus {ECO:0000250|UniProtKB:P08353}. Host nucleus, host CC nucleolus {ECO:0000250|UniProtKB:P08353}. Virion CC {ECO:0000250|UniProtKB:P08353}. Note=At early times in infection, CC colocalizes with PCNA and replication proteins in the host cell CC nucleus, before accumulating in the host cytoplasm by 8 to 12 hours CC post-infection. {ECO:0000250|UniProtKB:P08353}. CC -!- DOMAIN: The triplet repeats region may play a role in modulating virus CC egress. {ECO:0000250}. CC -!- MISCELLANEOUS: ICP34.5 is detected as early as 3 hpi prior to viral CC replication but reaches maximal levels late in infection. ICP34.5 gene CC is therefore classified as gamma-1 or leaky late gene. CC -!- MISCELLANEOUS: The phosphatase activity of the ICP34.5-PP1 complex CC toward EIF2S1 is specifically inhibited by Salubrinal, which inhibits CC viral replication. {ECO:0000250}. CC -!- SIMILARITY: Belongs to the PPP1R15 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X14112; CAA32285.1; -; Genomic_DNA. DR EMBL; X14112; CAA32348.1; -; Genomic_DNA. DR PIR; JQ1682; JQ1682. DR RefSeq; YP_009137073.1; NC_001806.2. DR RefSeq; YP_009137134.1; NC_001806.2. DR BioGRID; 971431; 16. DR BioGRID; 971432; 1. DR IntAct; P36313; 13. DR MINT; P36313; -. DR GeneID; 2703395; -. DR GeneID; 2703396; -. DR KEGG; vg:2703395; -. DR KEGG; vg:2703396; -. DR Proteomes; UP000009294; Genome. DR GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0044196; C:host cell nucleolus; IEA:UniProtKB-SubCell. DR GO; GO:0044423; C:virion component; IEA:UniProtKB-KW. DR GO; GO:0004865; F:protein serine/threonine phosphatase inhibitor activity; IEA:UniProtKB-KW. DR GO; GO:0039521; P:suppression by virus of host autophagy; IEA:UniProtKB-KW. DR GO; GO:0039606; P:suppression by virus of host translation initiation; IEA:UniProtKB-KW. DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW. DR GO; GO:0039548; P:suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity; IEA:UniProtKB-KW. DR PANTHER; PTHR16489; GH11727P; 1. DR PANTHER; PTHR16489:SF14; PROTEIN PHOSPHATASE 1 REGULATORY SUBUNIT 15A; 1. 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 IRF3 by virus; Inhibition of host RLR pathway by virus; KW Interferon antiviral system evasion; KW Modulation of host PP1 activity by virus; Reference proteome; Repeat; KW Viral immunoevasion; Virion; Virulence. FT CHAIN 1..248 FT /note="Neurovirulence factor ICP34.5" FT /id="PRO_0000115806" FT REPEAT 161..163 FT /note="1" FT REPEAT 164..166 FT /note="2" FT REPEAT 167..169 FT /note="3" FT REPEAT 170..172 FT /note="4" FT REPEAT 173..175 FT /note="5" FT REGION 1..129 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1..16 FT /note="Required for nucleolar localization" FT /evidence="ECO:0000250|UniProtKB:P08353" FT REGION 149..174 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 161..175 FT /note="5 X 3 AA tandem repeats of A-T-P" FT REGION 175..188 FT /note="Binding to PP1CA" FT /evidence="ECO:0000250|UniProtKB:P08353" FT REGION 175..188 FT /note="Interaction with host PPP1CA" FT /evidence="ECO:0000250|UniProtKB:P08353" FT REGION 190..248 FT /note="Important for interferon resistance" FT /evidence="ECO:0000250|UniProtKB:P08353" FT REGION 218..233 FT /note="Interaction with host EIF2S1/EIF-2ALPHA" FT /evidence="ECO:0000250|UniProtKB:P08353" FT MOTIF 128..137 FT /note="Nuclear export signal" FT /evidence="ECO:0000250|UniProtKB:P08353" FT MOTIF 200..218 FT /note="Bipartite nuclear localization signal" FT /evidence="ECO:0000250|UniProtKB:P08353" FT COMPBIAS 21..38 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 42..57 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 87..128 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" SQ SEQUENCE 248 AA; 26196 MW; BF216520CB379478 CRC64; MARRRRHRGP RRPRPPGPTG AVPTAQSQVT STPNSEPAVR SAPAAAPPPP PAGGPPPSCS LLLRQWLHVP ESASDDDDDD DWPDSPPPEP APEARPTAAA PRPRPPPPGV GPGGGADPSH PPSRPFRLPP RLALRLRVTA EHLARLRLRR AGGEGAPEPP ATPATPATPA TPATPARVRF SPHVRVRHLV VWASAARLAR RGSWARERAD RARFRRRVAE AEAVIGPCLG PEARARALAR GAGPANSV //