Deltex E3 ubiquitin ligase 3L is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the DTX3L

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. It functions as an

ubiquitin ligase A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...

(E3), and is over-expressed in chemotherapy-resistant lymphomas. It is a member of the DTX family of proteins. Among other roles it has a function in DNA damage repair. It was discovered through

two-hybrid screening Two-hybrid screening (originally known as yeast two-hybrid system or Y2H) is a molecular biology technique used to discover protein–protein interactions (PPIs) and DNA-binding protein#Protein–DNA interactions, protein–DNA interactions by t ...

during a search for binding partners of PARP9 (formerly BAL), a gene related to the risk of

B-cell lymphoma The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are Tumors of the hematopoietic and lymphoid tissues, "blood cancers" in the lymph nodes. They develop more frequently in older adults and in immunocompromised individuals. ...

. and was originally named BBAP (B-lymphoma- and BAL-associated protein). DTX3L and PARP9 are both located in the same 48kB region of the genome, and are both regulated by a

IFN-γ Interferon gamma (IFNG or IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. ...

-responsive bidirectional promoter. DTX3L has a long N-terminus domain distinct from other DTX-family proteins that allows it form dimers with itself and other proteins. It has been found to be up-regulated by METTL3.

Function

DTX3L functions as an

or E3. These proteins bind to ubiquitin-conjugating enzymes (E2s), and then transfer and bind the ubiquitin (activated by E1s) from the E2s to the target protein. Along with all other known DTX-family proteins (as of 2023), DTX3L is involved in the regulation of

Notch signaling The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transme ...

. DTX3L also plays a role in DNA damage repair, which has been associated with its ability to selectively mono-ubiquitylate (bind one ubiquitin to)

histone H4 Histone H4 is one of the five main histone proteins involved in the structure of chromatin in eukaryote, eukaryotic cells. Featuring a main globular domain and a long N-terminus, N-terminal tail, H4 is involved with the structure of the nucleo ...

. It helps to protect cells exposed to DNA damaging agents. DTX3L can form a complex with PARP9. This complex functions as a ubiquitin ligase and ubiquitinates both host histone H2BJ, to promote expression of interferon-stimulated genes, and viral 3C protease to disrupt viral assembly. This can help to control viral infection. PARP9 can also affect DXT3L's function in DNA damage repair. The DXT3L-PARP9 complex mediates mono-

ADP-ribosylation ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis ...

of ubiquitin; this prevents it from being conjugated and inhibits DXT3L's function as an ubiquitin ligase. The

NAD+ Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...

dependent binding of PARP9 to poly-ADP-ribose, instead, enhances the activity of DXT3L as a ubiquitin ligase. DTX3L can also form a complex with

DTX1 Protein deltex-1 is a protein that in humans is encoded by the ''DTX1'' gene. Function Studies in Drosophila have identified this gene as encoding a positive regulator of the notch signaling pathway. The human gene encodes a protein of unknown ...

. DTX3L also affects signaling by inhibiting the sorting of the

G-protein coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large protein family, group of evoluti ...

CXCR4 C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the ''CXCR4'' gene. The protein is a CXC chemokine receptor. Function CXCR-4 is an alpha- chemo ...

through the

endosomes Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of the endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membra ...

to degradation in the

lysosomes A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...

. When CXCR4 is activated, DXT3L localizes to early endosomes and inhibits the E3 ubiquitin ligase atrophin-1 interacting protein 4. This reduces the extent to which the protein ESCRT-0 is ubiquitinated, which reduces its ability to sort CXCR4 into the lysosomes. The implications of this effect (as of 2023) in cancer biology are unknown.

Function

References

Further reading