Host Protein General Information (ID: PT0369)
  Protein Name
E3 ubiquitin-protein ligase DTX3L (DTX3L)
  Gene Name
DTX3L
  Host Species
Homo sapiens
  Uniprot Entry Name
DTX3L_HUMAN
  Protein Families
Deltex family
  EC Number
2.3.2.27
  Subcellular Location
Cytoplasm and cytosol and endosome
  External Link
NCBI Gene ID
151636
Uniprot ID
Q8TDB6
Ensembl ID
ENSG00000163840
HGNC ID
HGNC:30323
  Function in Host
E3 ubiquitin-protein ligase which, in association with ADP-ribosyltransferase PARP9, plays a role in DNA damage repair and ininterferon-mediated antiviral responses. Monoubiquitinatesseveral histones, including histone H2A, H2B, H3 and H4. In response to DNA damage, mediatesmonoubiquitination of 'Lys-91' of histone H4 (H4K91ub1). The exact role of H4K91ub1 in DNA damage response isstill unclear but it may function as a licensing signal for additionalhistone H4 post-translational modifications such as H4 'Lys-20'methylation (H4K20me). PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites. By monoubiquitinating histone H2B H2BC9/H2BJ andthereby promoting chromatin remodeling, positively regulates STAT1-dependent interferon-stimulated gene transcription and thus STAT1-mediated control of viral replication. Independentlyof its catalytic activity, promotes the sorting of chemokine receptorCXCR4 from early endosome to lysosome following CXCL12 stimulation byreducing E3 ligase ITCH activity and thus ITCH-mediated ubiquitinationof endosomal sorting complex required for transport ESCRT-0 componentsHGS and STAM. In addition, required for therecruitment of HGS and STAM to early endosomes. Inassociation with PARP9, plays a role in antiviral responses bymediating 'Lys-48'-linked ubiquitination of encephalomyocarditis virus (EMCV) and human rhinovirus (HRV) C3 proteases and thus promoting theirproteosomal-mediated degradation. [1-5]
    Click to Show/Hide
  Related KEGG Pathway
Notch signaling pathway hsa04330            Pathway Map 
  3D Structure

Function of This Protein During Virus Infection
Virus NameSARS-COV-2 Protein Function Pro-viral [6]
Infected TissueLung Infection Time7-9 Days
Infected CellCalu-3 Cells (Human epithelial cell line) Cellosaurus IDCVCL_0609 
Method DescriptionTo detect the role of host protein DTX3L in viral infection, DTX3L protein knockout Calu-3 Cells were infected with SARS-COV-2 for 7 - 9 Days , and the effects on infection was detected through CRISPR-based genome-wide gene-knockout screen.
ResultsIt is reported that knockout of DTX3L leads to the decreased SARS-CoV-2 RNA levels compared with control group.

 Full List of Virus RNA Interacting with This Protien
            RNA Region: 5'-UTR (hCoV-19/Wuhan-Hu-1/2019 )
              RNA Region Details RNA Info Click to show the detail information of this RNA binding region [7]
              Strains Name
hCoV-19/Wuhan-Hu-1/2019
              Strains Family
Beta (B.1.351)
              RNA Binding Region
5'-UTR
              Virus Name
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
              Infection Cells HEK293 Cells (Human embryonic kidney cell)  (CVCL_0045 )
              Cell Originated Tissue Liver
              Infection Time 48 h
              Interaction Score Prot score = 18
              Method Description RNA-protein interaction detection (RaPID) assay; liquid chromatography with tandem mass spectrometry (LC-MS/MS)

Differential Gene Expression During SARS-COV-2 Infection
GEO Accession: GSE152641
Sample Type: Blood
Samples Details: Healthy Control: 24; COVID-19: 62
Platform: GPL24676 Illumina NovaSeq 6000
Picture Not Found

GEO Accession: GSE162835
Sample Type: Nasopharyngeal Swabs
Samples Details: COVID-19 (Mild Symptoms): 37; COVID-19 (Moderate Symptoms): 10; COVID-19 (Severe Symptoms): 3
Platform: GPL24676 Illumina NovaSeq 6000
Picture Not Found

GEO Accession: GSE175779
Sample Type: Human Bronchial Epithelial Cells
Samples Details: Healthy Control: 4 (0, 24, 48, 72 and 96 h); COVID-19: 4 (24, 48, 72 and 96 h)
Platform: GPL18573 Illumina NextSeq 500
Picture Not Found

Protein Phosphorylation after Virus Infection
S202 [8]
Picture Not Found
S221 [8]
Picture Not Found
S539 [8]
Picture Not Found
S9 [8]
Picture Not Found

Protein Sequence Information
MASHLRPPSPLLVRVYKSGPRVRRKLESYFQSSKSSGGGECTVSTQEHEAPGTFRVEFSERAAKERVLKKGEHQILVDEKPVPIFLVPTENSIKKNTRPQISSLTQSQAETPSGDMHQHEGHIPNAVDSCLQKIFLTVTADLNCNLFSKEQRAYITTLCPSIRKMEGHDGIEKVCGDFQDIERIHQFLSEQFLESEQKQQFSPSMTERKPLSQQERDSCISPSEPETKAEQKSNYFEVPLPYFEYFKYICPDKINSIEKRFGVNIEIQESSPNMVCLDFTSSRSGDLEAARESFASEFQKNTEPLKQECVSLADSKQANKFKQELNHQFTKLLIKEKGGELTLLGTQDDISAAKQKISEAFVKIPVKLFAANYMMNVIEVDSAHYKLLETELLQEISEIEKRYDICSKVSEKGQKTCILFESKDRQVDLSVHAYASFIDAFQHASCQLMREVLLLKSLGKERKHLHQTKFADDFRKRHPNVHFVLNQESMTLTGLPNHLAKAKQYVLKGGGMSSLAGKKLKEGHETPMDIDSDDSKAASPPLKGSVSSEASELDKKEKGICVICMDTISNKKVLPKCKHEFCAPCINKAMSYKPICPTCQTSYGIQKGNQPEGSMVFTVSRDSLPGYESFGTIVITYSMKAGIQTEEHPNPGKRYPGIQRTAYLPDNKEGRKVLKLLYRAFDQKLIFTVGYSRVLGVSDVITWNDIHHKTSRFGGPEMYGYPDPSYLKRVKEELKAKGIE
    Click to Show/Hide

References
1 Ubiquitin Modification by the E3 Ligase/ADP-Ribosyltransferase Dtx3L/Parp9. Mol Cell. 2017 May 18;66(4):503-516.e5.
2 PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection. Nat Immunol. 2015 Dec;16(12):1215-27.
3 BAL1 and its partner E3 ligase, BBAP, link Poly(ADP-ribose) activation, ubiquitylation, and double-strand DNA repair independent of ATM, MDC1, and RNF8. Mol Cell Biol. 2013 Feb;33(4):845-57.
4 BBAP monoubiquitylates histone H4 at lysine 91 and selectively modulates the DNA damage response. Mol Cell. 2009 Oct 9;36(1):110-20.
5 The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity. J Biol Chem. 2003 Jun 13;278(24):21930-7.
6 Genome-wide CRISPR screens identify GATA6 as a proviral host factor for SARS-CoV-2 via modulation of ACE2. Nat Commun. 2022 Apr 25;13(1):2237.
7 RNA-Protein Interaction Analysis of SARS-CoV-2 5 and 3 Untranslated Regions Reveals a Role of Lysosome-Associated Membrane Protein-2a during Viral Infection. mSystems. 2021 Aug 31;6(4):e0064321.
8 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature. 2021 Jun;594(7862):246-252.