ID   UL38_HCMVM              Reviewed;         331 AA.
AC   F5HG98;
DT   13-JUN-2012, integrated into UniProtKB/Swiss-Prot.
DT   28-JUN-2011, sequence version 1.
DT   23-FEB-2022, entry version 25.
DE   RecName: Full=Apoptosis inhibitor UL38;
GN   Name=UL38;
OS   Human cytomegalovirus (strain Merlin) (HHV-5) (Human herpesvirus 5).
OC   Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes;
OC   Herpesvirales; Herpesviridae; Betaherpesvirinae; Cytomegalovirus.
OX   NCBI_TaxID=295027;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15105547; DOI=10.1099/vir.0.79888-0;
RA   Dolan A., Cunningham C., Hector R.D., Hassan-Walker A.F., Lee L.,
RA   Addison C., Dargan D.J., McGeoch D.J., Gatherer D., Emery V.C.,
RA   Griffiths P.D., Sinzger C., McSharry B.P., Wilkinson G.W.G., Davison A.J.;
RT   "Genetic content of wild-type human cytomegalovirus.";
RL   J. Gen. Virol. 85:1301-1312(2004).
RN   [2]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=17202209; DOI=10.1128/jvi.02124-06;
RA   Terhune S., Torigoi E., Moorman N., Silva M., Qian Z., Shenk T., Yu D.;
RT   "Human cytomegalovirus UL38 protein blocks apoptosis.";
RL   J. Virol. 81:3109-3123(2007).
RN   [3]
RP   FUNCTION, AND INTERACTION WITH HOST TSC2.
RX   PubMed=18407068; DOI=10.1016/j.chom.2008.03.002;
RA   Moorman N.J., Cristea I.M., Terhune S.S., Rout M.P., Chait B.T., Shenk T.;
RT   "Human cytomegalovirus protein UL38 inhibits host cell stress responses by
RT   antagonizing the tuberous sclerosis protein complex.";
RL   Cell Host Microbe 3:253-262(2008).
RN   [4]
RP   FUNCTION.
RX   PubMed=21715486; DOI=10.1128/jvi.00572-11;
RA   Qian Z., Xuan B., Gualberto N., Yu D.;
RT   "The human cytomegalovirus protein pUL38 suppresses endoplasmic reticulum
RT   stress-mediated cell death independently of its ability to induce mTORC1
RT   activation.";
RL   J. Virol. 85:9103-9113(2011).
RN   [5]
RP   FUNCTION, AND INTERACTION WITH HOST USP24.
RX   PubMed=29695420; DOI=10.1128/jvi.00191-18;
RA   Sun Y., Bao Q., Xuan B., Xu W., Pan D., Li Q., Qian Z.;
RT   "Human Cytomegalovirus Protein pUL38 Prevents Premature Cell Death by
RT   Binding to Ubiquitin-specific Protease 24 and Regulating Iron Metabolism.";
RL   J. Virol. 0:0-0(2018).
CC   -!- FUNCTION: Plays a role in the inhibition of host apoptosis to
CC       facilitate efficient viral replication. Promotes stabilization and
CC       inactivation of host TP53 through interaction with host MDM2 (By
CC       similarity). Induces host mTORC1 activation by antagonizing the ability
CC       of host TSC1/2 to negatively regulate mTORC1. Thus, inhibits a growth
CC       regulatory pathway to facilitate viral replication. Prevents premature
CC       cell host cell death by blocking host ubiquitin-specific protease
CC       24/USP24-mediated autophagic ferritin degradation in lysosomes thus
CC       maintaining lysosome integrity and cellular viability
CC       (PubMed:29695420). {ECO:0000250|UniProtKB:Q9WT45,
CC       ECO:0000269|PubMed:17202209, ECO:0000269|PubMed:18407068,
CC       ECO:0000269|PubMed:21715486, ECO:0000269|PubMed:29695420}.
CC   -!- SUBUNIT: Interacts with host MDM2; this interaction leads to the
CC       stabilization of host TP53 (By similarity). Interacts with host TSC2;
CC       this interaction prevents host cell stress responses. Interacts with
CC       host USP24. {ECO:0000250|UniProtKB:Q9WT45,
CC       ECO:0000269|PubMed:18407068}.
CC   -!- SUBCELLULAR LOCATION: Host cytoplasm {ECO:0000269|PubMed:17202209}.
CC       Host nucleus {ECO:0000269|PubMed:17202209}. Note=localized in the host
CC       nucleus at early times postinfection and then increases in both nuclear
CC       and cytoplasmic compartments during the course of infection.
CC   -!- SIMILARITY: Belongs to the beta-herpesvirinae UL38 protein family.
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DR   EMBL; AY446894; AAR31603.1; -; Genomic_DNA.
DR   RefSeq; YP_081497.1; NC_006273.2.
DR   PRIDE; F5HG98; -.
DR   DNASU; 3077531; -.
DR   GeneID; 3077531; -.
DR   KEGG; vg:3077531; -.
DR   Reactome; R-HSA-9609690; HCMV Early Events.
DR   Reactome; R-HSA-9610379; HCMV Late Events.
DR   Proteomes; UP000000938; 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:0019033; C:viral tegument; TAS:Reactome.
DR   GO; GO:0039526; P:modulation by virus of host apoptotic process; IEA:UniProtKB-KW.
DR   InterPro; IPR003360; US22-like.
DR   Pfam; PF02393; US22; 1.
PE   1: Evidence at protein level;
KW   Host cytoplasm; Host nucleus; Host-virus interaction;
KW   Modulation of host cell apoptosis by virus; Reference proteome.
FT   CHAIN           1..331
FT                   /note="Apoptosis inhibitor UL38"
FT                   /id="PRO_0000417845"
FT   REGION          246..309
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        280..303
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ   SEQUENCE   331 AA;  36753 MW;  533D3F344DDBBB54 CRC64;
     MTTTTHSTAA IMSLLDEAEW RQTQMDVGGL IQASALGKVA LRYAVRKLMK RGARLRHDSG
     LYVCICDPSY EFLQMNLSKI SWLERHCPPL DQELIMFGVI EAWEEASVRP TRQLVLFMTP
     KWDVFAYDSG ILFFLAPSMA QFWHGAIVLE YWNALFPVEV RSHVRQHAHT MDDLVMVFHQ
     LDYEKQVLEA RRDKNTEGPR TFAKSVNSYV RAILESERRI REGKIPMTFV DRDSLRANSL
     AHIQATGAQP SHAPAQRVLS APPSLPSPVS EEDPAAAATP PSSAATTPPS SVVPASVESE
     LSSSPPLPPV VVKDVMYTAG EGDVVQMVVV V