New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

Abstract

HECT E3 ubiquitin ligases selectively recognize, bind, and ubiquitylate their substrate proteins to target them for 26S proteasomal degradation. There is increasing evidence that HECT E3 ubiquitin ligase dysfunction due to misfolding and/or the gene encoding the protein being mutated is responsible for the development of different diseases. Apart from the more prominent and well-characterized E6AP and members of the NEDD4 family, new studies have begun to reveal how other members of the HECT E3 ubiquitin ligase family function as well as their links to disease and developmental disorders. This chapter provides a comprehensive discussion on the more mysterious members of the HECT E3 ubiquitin ligase family and how they control intracellular processes. Specifically, AREL1, HACE1, HECTD1, HECTD4, G2E3, and TRIP12 will be examined as these enzymes have recently been identified as contributors to disease development.2 covalently attach ubiquitin on to a lysine residue of the substrate protein forming a stable isopeptide bond between the C-terminus of ubiquitin and the ε-amine of the substrate lysine [3,5,6]. This process can be repeated numerous times to form different polyubiquitin chain linkages with the specific HECT E3 ubiquitin ligase dictating the type(s) of ubiquitin linkages that are built [2,7]. Chain typesLinker Proposed function Monoubiquitylation Monoubiquitylation/ multi-monoubiquitylation Endocytosis [9] DNA damage repair [10-15] Histone regulation [10-15] Mitophagy [10-15] Protein localization [10-15] Protein interactions [10-15] Protein transportation [10-15] Transcription activation [10-15] Polyubiquitylation Chain (homotypic) M1 Innate immunity [2, 9, 16] Linear chain formation [9] NF-κB activation [9, 16] Signaling cascades [9, 16] K6 DNA damage response [14] NF-κB regulation [14] Mitophagy [14] K11 Cell cycle regulation [17] DNA damage response [18] Mitophagy [17] NF-κB activation [16] Protein degradation [17] K27 DNA damage response [18] Kinase activation [19] Protein degradation [20] Protein scaffolding [21] Protein trafficking [22] K29 DNA damage response [18] Kinase activation [19] Protein degradation [9] K33 DNA damage response [10-15, 18] Kinase activation [23] Post-golgi trafficking [24] T-cell signaling [23] K4 8 Protein degradation [1, 2, 25] K63 DNA damage response [9, 18] NF-κB activation [9, 16] Protein trafficking [9] Chain (heterotypic; branched) M1 /K63 NF-κB activation [16] K11 /K4 8 Protein degradation [26, 27] K29/K48 Protein degradation [26] K48/K63 Protein degradation [26] K11 /K63 Endocytosis [28]

A Novel Prognostic Biomarker with Potential of High Diagnostic Accuracy in Pulmonary Tuberculosis: An in silico Study

“…Interestingly increasing evidence has suggested the role of the HECT E3 domain in disease development. 51,52 Altered functioning of TRIP12 due to down-regulation or mutation may lead to disease development. Thus, it can be hypothesized that TRIP12 might be involved in the degradation of MTB, and its downregulation may cause the development of tuberculosis (Figure 8).…”

Structural Insights into Ankyrin Repeat-Containing Proteins and Their Influence in Ubiquitylation

“…Alternative polyubiquitin chains with different linkages have also been shown to regulate cellular processes. These include K6, K27, K29 and K63 polyubiquitylation to initiate the DNA damage response [ 26 ]; M1 and K11 polyubiquitin to activate the NF-κβ signaling pathway [ 26 ]; and various branched polyubiquitylation chains (i.e., K11/K48, K29/K48, K48/K63) have been observed to target proteins for proteolysis [ 27 ]. The complexity and permutations of ubiquitin chain types can include the modification of ubiquitin residues such as lysine acetylation that can repress K6 and K48 polyubiquitin chain formation [ 25 ], and serine/threonine phosphorylation that can act as an activator of the RBR E3 ubiquitin ligase parkin [ 28 ].…”