Deltex (DTX) proteins have been considered putative E3 ligases, based on the presence of an E3 RING domain in their protein coding sequence. The human DTX family includes DTX1, DTX2, DTX3, DTX3L and DTX4. Despite the fact that peourple's knowledge of this class of E3-ubiquitin ligases is still at an early stage, ourthe understanding of their role in oncogenesis is beginning to unfold. In fact, recently published studies allow us to define specific biological scenarios and further consolidate evidence-based working hypotheses.
1. Introduction
RING (Really Interesting New Gene) Fingers (RNF) domain-containing proteins constitute the most widely represented type of E3 ubiquitin ligases in the human genome. They are involved both in the regulation of targeted-proteins’ function as well as in ubiquitin proteasome system (UPS)-mediated degradation (reviewed by
[1]). RING finger domains found in RNF proteins bind two zinc ions in a “cross-brace” fashion involving a distinctive cysteine and histidine residue-containing motif, a feature previously known to be shared only by zinc-finger DNA-binding proteins
[2]. Despite some DTX proteins having been found overexpressed in cancer, their mechanistic involvement in the underlying pathological process is still at an early stage of investigation
[3]. Most ubiquitin E3 ligases (UbE3L) studied until recently had been found to be involved in the N-degradation pathway responsible for recruiting specific UbE3L to the targeted proteins’ N-terminal region
[4]. Recently, a growing number of C-Degrons-bearing proteins have been identified, along with the underlying UbE3L-driven degradation complexes (reviewed by Varshawsky
[5]). The relatively recent field of C-Degron pathways had lead some authors to define this type of degradation mechanism with the acronym of “DesCEnd” (from “Destruction by the C-End”)
[6]. Although to date the RING motifs in DTX proteins have not been restricted to either of the N-Degron or C-Degron degradation pathways, the recently described involvement of DTX3c in the specific recruitment to the EphB4 C-
pi (phospho-inhibited) Degron
[7,8][7][8] assigns DTX3 to the C-Degron pathway.
2. DTX Proteins Structural and Functional Features: Phylogenetic and Intra-Species Considerations
DTX protein expression is almost ubiquitous in mammalians, although they display the highest expression in specific cell and tissue types like blood vessels, embryonic neural tissues, genital and reproductive apparatus, pancreas, lungs, liver, kidneys, adrenal gland, skin, intestinal epithelial components and muscle (see Uberon Anatomy Ontology at
https://bioportal.bioontology.org/ontologies/UBERON accessed on 17 May 2023
[9]). A first hint at the physiological role of DTX proteins has come from a DTX
Drosophila gene null mutant study which confirmed the tissue-specific requirement for DTX expression and its dispensable role in embryo development
[10]. This is consistent with the finding that T-cells, a DTX1 and 2 expressing mammalian cell type, can develop normally in absence of both DTX1 and DTX2
[11]. On the other hand, overexpression of DTX proteins in mammalian systems has been found to affect myogenesis, neurogenesis
[12] and the proper function of lymphoid organs
[13]. More recently, DTX protein expression in cancer cells has revealed a wide landscape of contextual functions linked, in part, to their regulation of NOTCH signaling. As graphically summarized in
Figure 1, mammalian DTX proteins share all or part of the
Drosophila DTX (dDTX) progenitor structure
[12,14][12][14]. As such, some phylogenetic and intra-species key comparative points can be made per each
Drosophila reference domain structure in order to better understand the emerging cellular and systemic functions of DTX proteins in mammalians. In particular, human DTX proteins are linked to the expression of five paralog genes along with their main isoform variants (
Table 1 and
Figure 1). A number of human isoform variants have been reported for DTX proteins (
Figure 1). These are discussed below in relationship with the underlying protein domain features.
Figure 1. The Drosophila and human DTX protein domain structure. WWE, WWE tandem domains; DTX3-NTa, DTX3a N-Terminal variant (isoform 1); DTX3-NTb, DTX3b N-Terminal variant (isoform 2), D, D-Domain; H2-RING, canonical Ring finger motif (H2)-containing domain; HC-RING, C3HC4 finger motif-containing domain; DTC, Deltex C-Terminal Domain. DTX3c N-Terminal domain retains both 1a and 1b exons to generate a new isoform (isoform 3) with N-terminus 3D unique distribution differing from the canonical DTX3a and DTX3b isoforms.
Table 1.
Human DTX genes and relative products features
1
.