ID   X_HBVD3                 Reviewed;         154 AA.
AC   P03165;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   01-APR-1990, sequence version 2.
DT   04-NOV-2026, entry version 111.
DE   RecName: Full=Protein X {ECO:0000255|HAMAP-Rule:MF_04074};
DE   AltName: Full=HBx {ECO:0000255|HAMAP-Rule:MF_04074};
DE   AltName: Full=Peptide X {ECO:0000255|HAMAP-Rule:MF_04074};
DE   AltName: Full=pX {ECO:0000255|HAMAP-Rule:MF_04074};
GN   Name=X {ECO:0000255|HAMAP-Rule:MF_04074};
OS   Hepatitis B virus genotype D subtype ayw (isolate France/Tiollais/1979)
OS   (HBV-D).
OC   Viruses; Riboviria; Pararnavirae; Artverviricota; Revtraviricetes;
OC   Blubervirales; Hepadnaviridae; Orthohepadnavirus;
OC   Orthohepadnavirus hominoidei; Hepatitis B virus;
OC   hepatitis B virus genotype D.
OX   NCBI_TaxID=490133;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
OH   NCBI_TaxID=9598; Pan troglodytes (Chimpanzee).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=399327; DOI=10.1038/281646a0;
RA   Galibert F., Mandart E., Fitoussi F., Tiollais P., Charnay P.;
RT   "Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned
RT   in E. coli.";
RL   Nature 281:646-650(1979).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=Latvia;
RX   PubMed=3996597; DOI=10.1016/0014-5793(85)80771-7;
RA   Bichko V., Pushko P., Dreilina D., Pumpen P., Gren E.Y.;
RT   "Subtype ayw variant of hepatitis B virus. DNA primary structure
RT   analysis.";
RL   FEBS Lett. 185:208-212(1985).
RN   [3]
RP   CHARACTERIZATION.
RX   PubMed=9328333; DOI=10.1002/hep.510260437;
RA   Urban S., Hildt E., Eckerskorn C., Sirma H., Kekule A., Hofschneider P.H.;
RT   "Isolation and molecular characterization of hepatitis B virus X-protein
RT   from a baculovirus expression system.";
RL   Hepatology 26:1045-1053(1997).
RN   [4]
RP   INTERACTION WITH HUMAN DDB1, AND MUTAGENESIS OF 77-ARG-ARG-78; LYS-91;
RP   95-LYS-ARG-96; LEU-98; ASP-107 AND 113-LYS-ASP-114.
RC   STRAIN=Switzerland/Strubin/1999;
RX   PubMed=11531405; DOI=10.1006/viro.2001.1036;
RA   Lin-Marq N., Bontron S., Leupin O., Strubin M.;
RT   "Hepatitis B virus X protein interferes with cell viability through
RT   interaction with the p127-kDa UV-damaged DNA-binding protein.";
RL   Virology 287:266-274(2001).
RN   [5]
RP   INTERACTION WITH HUMAN DDB1.
RC   STRAIN=Switzerland/Strubin/1999;
RX   PubMed=12151405; DOI=10.1074/jbc.m205722200;
RA   Bontron S., Lin-Marq N., Strubin M.;
RT   "Hepatitis B virus X protein associated with UV-DDB1 induces cell death in
RT   the nucleus and is functionally antagonized by UV-DDB2.";
RL   J. Biol. Chem. 277:38847-38854(2002).
RN   [6]
RP   INTERACTION WITH HUMAN DDB1.
RC   STRAIN=Switzerland/Strubin/1999;
RX   PubMed=12743284; DOI=10.1128/jvi.77.11.6274-6283.2003;
RA   Leupin O., Bontron S., Strubin M.;
RT   "Hepatitis B virus X protein and simian virus 5 V protein exhibit similar
RT   UV-DDB1 binding properties to mediate distinct activities.";
RL   J. Virol. 77:6274-6283(2003).
RN   [7]
RP   FUNCTION.
RC   STRAIN=Switzerland/Strubin/1999;
RX   PubMed=15767425; DOI=10.1128/jvi.79.7.4238-4245.2005;
RA   Leupin O., Bontron S., Schaeffer C., Strubin M.;
RT   "Hepatitis B virus X protein stimulates viral genome replication via a
RT   DDB1-dependent pathway distinct from that leading to cell death.";
RL   J. Virol. 79:4238-4245(2005).
RN   [8]
RP   INTERACTION WITH E4F1.
RX   PubMed=16112766; DOI=10.1016/j.virusres.2005.07.003;
RA   Rui E., Moura P.R., Goncalves K.A., Rooney R.J., Kobarg J.;
RT   "Interaction of the hepatitis B virus protein HBx with the human
RT   transcription regulatory protein p120E4F in vitro.";
RL   Virus Res. 115:31-42(2006).
RN   [9]
RP   REVIEW.
RX   PubMed=15542625; DOI=10.1128/jvi.78.23.12725-12734.2004;
RA   Bouchard M.J., Schneider R.J.;
RT   "The enigmatic X gene of hepatitis B virus.";
RL   J. Virol. 78:12725-12734(2004).
RN   [10]
RP   REVIEW.
RX   PubMed=16984372; DOI=10.1111/j.1349-7006.2006.00299.x;
RA   Tang H., Oishi N., Kaneko S., Murakami S.;
RT   "Molecular functions and biological roles of hepatitis B virus x protein.";
RL   Cancer Sci. 97:977-983(2006).
CC   -!- FUNCTION: Multifunctional protein that plays a role in silencing host
CC       antiviral defenses and promoting viral transcription. Does not seem to
CC       be essential for HBV infection. May be directly involved in development
CC       of cirrhosis and liver cancer (hepatocellular carcinoma). Most of
CC       cytosolic activities involve modulation of cytosolic calcium. The
CC       effect on apoptosis is controversial depending on the cell types in
CC       which the studies have been conducted. May induce apoptosis by
CC       localizing in mitochondria and causing loss of mitochondrial membrane
CC       potential. May also modulate apoptosis by binding host CFLAR, a key
CC       regulator of the death-inducing signaling complex (DISC). Promotes
CC       viral transcription by using the host E3 ubiquitin ligase DDB1 to
CC       target the SMC5-SMC6 complex to proteasomal degradation. This host
CC       complex would otherwise bind to viral episomal DNA, and prevents its
CC       transcription. Moderately stimulates transcription of many different
CC       viral and cellular transcription elements. Promoters and enhancers
CC       stimulated by HBx contain DNA binding sites for NF-kappa-B, AP-1, AP-2,
CC       c-EBP, ATF/CREB, or the calcium-activated factor NF-AT.
CC       {ECO:0000255|HAMAP-Rule:MF_04074, ECO:0000269|PubMed:15767425}.
CC   -!- SUBUNIT: May form homodimer. May interact with host CEBPA, CFLAR,
CC       CREB1, DDB1, E4F1, HBXIP, HSPD1/HSP60, NFKBIA, POLR2E and SMAD4.
CC       Interacts with host SMC5-SMC6 complex and induces its degradation.
CC       Interacts with host TRPC4AP; leading to prevent ubiquitination of
CC       TRPC4AP. Interacts with host PLSCR1; this interaction promotes
CC       ubiquitination and degradation of HBx and impairs HBx-mediated cell
CC       proliferation. {ECO:0000255|HAMAP-Rule:MF_04074}.
CC   -!- INTERACTION:
CC       P03165; P31749: AKT1; Xeno; NbExp=3; IntAct=EBI-7683985, EBI-296087;
CC       P03165; P31750: Akt1; Xeno; NbExp=2; IntAct=EBI-7683985, EBI-298707;
CC   -!- SUBCELLULAR LOCATION: Host cytoplasm {ECO:0000255|HAMAP-Rule:MF_04074}.
CC       Host nucleus {ECO:0000255|HAMAP-Rule:MF_04074}. Host mitochondrion
CC       {ECO:0000255|HAMAP-Rule:MF_04074}. Note=Mainly cytoplasmic as only a
CC       fraction is detected in the nucleus. In cytoplasm, a minor fraction
CC       associates with mitochondria or proteasomes. {ECO:0000255|HAMAP-
CC       Rule:MF_04074}.
CC   -!- PTM: A fraction may be phosphorylated in insect cells and HepG2 cells,
CC       a human hepatoblastoma cell line. Phosphorylated in vitro by host
CC       protein kinase C or mitogen-activated protein kinase. N-acetylated in
CC       insect cells. {ECO:0000255|HAMAP-Rule:MF_04074}.
CC   -!- SIMILARITY: Belongs to the orthohepadnavirus protein X family.
CC       {ECO:0000255|HAMAP-Rule:MF_04074}.
CC   -!- CAUTION: Transcriptional activities should be taken with a grain of
CC       salt. As of 2007, all studies demonstrating in vivo interaction between
CC       protein X and transcriptional components were performed with
CC       significant overexpression of both proteins and in the absence of viral
CC       infection.
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DR   EMBL; V01460; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; X02496; CAB41697.1; -; Genomic_DNA.
DR   PIR; A03719; QQVLD1.
DR   PIR; A05237; QQVLBH.
DR   SMR; P03165; -.
DR   IntAct; P03165; 4.
DR   iPTMnet; P03165; -.
DR   Proteomes; UP000007930; Segment.
DR   GO; GO:0033650; C:host cell mitochondrion; IEA:UniProtKB-SubCell.
DR   GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0006351; P:DNA-templated transcription; IEA:UniProtKB-UniRule.
DR   GO; GO:0085033; P:symbiont-mediated activation of host NF-kappaB cascade; IEA:UniProtKB-UniRule.
DR   GO; GO:0039592; P:symbiont-mediated arrest of host cell cycle during G2/M transition; IEA:UniProtKB-UniRule.
DR   GO; GO:0019079; P:viral genome replication; IEA:UniProtKB-UniRule.
DR   HAMAP; MF_04074; HBV_X; 1.
DR   InterPro; IPR000236; Transactivation_prot_X.
DR   Pfam; PF00739; X; 1.
PE   1: Evidence at protein level;
KW   Activation of host NF-kappa-B by virus; Activator; Apoptosis;
KW   Host cytoplasm; Host G2/M cell cycle arrest by virus; Host mitochondrion;
KW   Host nucleus; Host-virus interaction;
KW   Modulation of host cell cycle by virus; Reference proteome; Transcription;
KW   Transcription regulation.
FT   CHAIN           1..154
FT                   /note="Protein X"
FT                   /id="PRO_0000222361"
FT   REGION          68..117
FT                   /note="Mitochondrial targeting sequence"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04074"
FT   VARIANT         26
FT                   /note="R -> C (in strain: Switzerland/Strubin/1999)"
FT   VARIANT         33
FT                   /note="S -> P (in strain: Switzerland/Strubin/1999)"
FT   VARIANT         36
FT                   /note="T -> A (in strain: Switzerland/Strubin/1999)"
FT   VARIANT         40..43
FT                   /note="PSPS -> SSLP (in strain: Switzerland/Strubin/1999)"
FT   VARIANT         46
FT                   /note="P -> S (in strain: Latvia)"
FT   VARIANT         47..48
FT                   /note="TD -> AA (in strain: Switzerland/Strubin/1999)"
FT   VARIANT         84..88
FT                   /note="NAHQI -> KAQPF (in strain: Latvia)"
FT   VARIANT         102
FT                   /note="A -> V (in strain: Latvia)"
FT   MUTAGEN         77..78
FT                   /note="RR->EE: No effect on interaction with human DDB1."
FT                   /evidence="ECO:0000269|PubMed:11531405"
FT   MUTAGEN         91
FT                   /note="K->E: No effect on interaction with human DDB1."
FT                   /evidence="ECO:0000269|PubMed:11531405"
FT   MUTAGEN         95
FT                   /note="K->E: No effect on interaction with human DDB1."
FT   MUTAGEN         96
FT                   /note="R->E: Complete loss of interaction with human DDB1."
FT   MUTAGEN         98
FT                   /note="L->F: Complete loss of interaction with human DDB1."
FT                   /evidence="ECO:0000269|PubMed:11531405"
FT   MUTAGEN         107
FT                   /note="D->R: No effect on interaction with human DDB1."
FT                   /evidence="ECO:0000269|PubMed:11531405"
FT   MUTAGEN         113..114
FT                   /note="KD->ER: No effect on interaction with human DDB1."
FT                   /evidence="ECO:0000269|PubMed:11531405"
SQ   SEQUENCE   154 AA;  16618 MW;  29FD1CC9E09A34B5 CRC64;
     MAARLCCQLD PARDVLCLRP VGAESRGRPF SGSLGTLSSP SPSAVPTDHG AHLSLRGLPV
     CAFSSAGPCA LRFTSARRME TTVNAHQILP KVLHKRTLGL SAMSTTDLEA YFKDCLFKDW
     EELGEEIRLK VFVLGGCRHK LVCAPAPCNF FTSA
//