E3 Ubiquitin Ligase TRIP12: Regulation, Structure, and Physiopathological Functions

Abstract

The Thyroid hormone Receptor Interacting Protein 12 (TRIP12) protein belongs to the 28-member Homologous to the E6-AP C-Terminus (HECT) E3 ubiquitin ligase family. First described as an interactor of the thyroid hormone receptor, TRIP12’s biological importance was revealed by the embryonic lethality of a murine model bearing an inactivating mutation in the TRIP12 gene. Further studies showed the participation of TRIP12 in the regulation of major biological processes such as cell cycle progression, DNA damage repair, chromatin remodeling, and cell differentiation by an ubiquitination-mediated degradation of key protein substrates. Moreover, alterations of TRIP12 expression have been reported in cancers that can serve as predictive markers of therapeutic response. The TRIP12 gene is also referenced as a causative gene associated to intellectual disorders such as Clark–Baraitser syndrome and is clearly implicated in Autism Spectrum Disorder. The aim of the review is to provide an exhaustive and integrated overview of the different aspects of TRIP12 ranging from its regulation, molecular functions and physio-pathological implications.

Glutamine antagonist JHU083 improves psychosocial behavior and sleep deficits in EcoHIV-infected mice

“…A target of Trip12, ADP ribosylation factors (ARF) are better characterized in cancer, but they have also been shown to regulate neuronal survival in the hippocampus ( Kim et al, 2020 ), thereby suggesting a potential procognitive pathway. Although studies linking Trip12 haploinsufficiency to intellectual disability ( Brunet et al, 2020 ) are inverse to our findings, it is possible that any expression outside of a normal range could be pathogenic. Beyond the immune pathways, Dnmt3a, a DNA methyltransferase, was significantly reduced in EcoHIV-infected mice and normalized with JHU083 treatment.…”

“…However, previous studies have shown that treatment of EcoHIV-infected mice with the JHU083 parent drug DON does not decrease viral load ( Nedelcovych et al, 2017b ), so it is likely that any direct antiviral effects of JHU083 are muted by the fact that the drug also suppresses T cell activity ( Hollinger et al, 2019 ; Baxter et al, 2017 ) and that neurobehavioral changes are through a secondary mechanism. Trip12 is a ubiquitin ligase, and its overexpression has been found in cancer and bacterial infections ( Brunet et al, 2020 ). A target of Trip12, ADP ribosylation factors (ARF) are better characterized in cancer, but they have also been shown to regulate neuronal survival in the hippocampus ( Kim et al, 2020 ), thereby suggesting a potential procognitive pathway.…”

Helicobacter pylori pathogen inhibits cellular responses to oncogenic stress and apoptosis

“…suppression of host immune responses caused by apoptotic signaling [ 25 ]. However, it may also have a tumor-promoting effect as GC and many other human tumors are characterized by upregulation of ULF and inhibition of p14ARF [ 26 ]. This concept is in agreement with our findings showing that ARF knockout mice infected with H .…”

Case Report: Immune Microenvironment and Mutation Features in a Patient With Epstein–Barr Virus Positive Large B-Cell Lymphoma Secondary to Angioimmunoblastic T-Cell Lymphoma

“…As mentioned above, mutations in EBV + DLBCL most popularly affect the JAK/STAT signaling, and we consider that JAK/STAT inhibitions may be attractive drugs for therapeutic intervention of EBV + DLBCL (Meyer and Levine, 2014). TRIP12 (thyroid hormone receptor interacting protein 12), as a member of the structurally and functionally related E3 ubiquitin ligases, plays important roles in carcinogenesis through regulating the ubiquitination of key proteins (Brunet et al, 2020). Through describing the mutation profiles of this case, we conjecture JAK2 and TRIP12 mutations might be the indicators to predict the transformation of AITL to LBCL.…”