The E3 Ubiquitin Ligase TRAF6 Interacts with the Cellular Prion Protein and Modulates Its Solubility and Recruitment to Cytoplasmic p62/SQSTM1-Positive Aggresome-Like Structures

Masperone, Lara; Codrich, Marta; Persichetti, Francesca; Gustincich, Stefano; Zucchelli, S.; Legname, Giuseppe

doi:10.1007/s12035-021-02666-6

Cited by 4 publications

(3 citation statements)

References 66 publications

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“…Recently, p62/SQSTM1 was found in cytoplasmic inclusions together with PrP C and the E3-ligase/TRAF6. Moreover, its activity was required for proper redistribution of PrP C into the insoluble cell fraction suggesting a novel physiological interaction between p62/SQSTM1 and PrP C ( Masperone et al, 2022 ). Recent evidence suggested that neurodegeneration in prion diseases may be the consequence of defective glia as astrocytes have been shown to deposit mutant PrP aggregates and propagate prions to neurons and other cells (seed effect; Tahir et al, 2022 ).…”

Section: Neurodegenerative Proteinopathies or (Pps)mentioning

confidence: 99%

Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies

et al. 2023

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Proteinopathies are a large group of neurodegenerative diseases caused by both genetic and sporadic mutations in particular genes which can lead to alterations of the protein structure and to the formation of aggregates, especially toxic for neurons. Autophagy is a key mechanism for clearing those aggregates and its function has been strongly associated with the ubiquitin-proteasome system (UPS), hence mutations in both pathways have been associated with the onset of neurodegenerative diseases, particularly those induced by protein misfolding and accumulation of aggregates. Many crucial discoveries regarding the molecular and cellular events underlying the role of autophagy in these diseases have come from studies using Drosophila models. Indeed, despite the physiological and morphological differences between the fly and the human brain, most of the biochemical and molecular aspects regulating protein homeostasis, including autophagy, are conserved between the two species.In this review, we will provide an overview of the most common neurodegenerative proteinopathies, which include PolyQ diseases (Huntington’s disease, Spinocerebellar ataxia 1, 2, and 3), Amyotrophic Lateral Sclerosis (C9orf72, SOD1, TDP-43, FUS), Alzheimer’s disease (APP, Tau) Parkinson’s disease (a-syn, parkin and PINK1, LRRK2) and prion diseases, highlighting the studies using Drosophila that have contributed to understanding the conserved mechanisms and elucidating the role of autophagy in these diseases.

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Section: Neurodegenerative Proteinopathies or (Pps)mentioning

confidence: 99%

Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies

et al. 2023

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“…In vitro studies, performed in cell lines expressing PrP mutant forms, have demonstrated that the pharmacological inhibition of UPS induces intracellular accumulation of detergent-insoluble and partially protease-resistant PrP that accumulates in aggregation bodies (Zanusso et al, 1999 ; Jin et al, 2000 ; Ma and Lindquist, 2001 ; Mishra et al, 2003 ). Moreover, the ubiquitinylation of PrP C by the ubiquitin ligase TRAF6 favors its interaction with p62 and the formation of aggresomes (Masperone et al, 2022 ).…”

Section: Protein Quality Control Of Prion Proteinmentioning

confidence: 99%

Proteostasis unbalance in prion diseases: Mechanisms of neurodegeneration and therapeutic targets

et al. 2022

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Transmissible spongiform encephalopathies (TSEs), or prion diseases, are progressive neurodegenerative disorders of the central nervous system that affect humans and animals as sporadic, inherited, and infectious forms. Similarly to Alzheimer's disease and other neurodegenerative disorders, any attempt to reduce TSEs' lethality or increase the life expectancy of affected individuals has been unsuccessful. Typically, the onset of symptoms anticipates the fatal outcome of less than 1 year, although it is believed to be the consequence of a decades-long process of neuronal death. The duration of the symptoms-free period represents by itself a major obstacle to carry out effective neuroprotective therapies. Prions, the infectious entities of TSEs, are composed of a protease-resistant protein named prion protein scrapie (PrPSc) from the prototypical TSE form that afflicts ovines. PrPSc misfolding from its physiological counterpart, cellular prion protein (PrPC), is the unifying pathogenic trait of all TSEs. PrPSc is resistant to intracellular turnover and undergoes amyloid-like fibrillation passing through the formation of soluble dimers and oligomers, which are likely the effective neurotoxic entities. The failure of PrPSc removal is a key pathogenic event that defines TSEs as proteopathies, likewise other neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, characterized by alteration of proteostasis. Under physiological conditions, protein quality control, led by the ubiquitin-proteasome system, and macroautophagy clears cytoplasm from improperly folded, redundant, or aggregation-prone proteins. There is evidence that both of these crucial homeostatic pathways are impaired during the development of TSEs, although it is still unclear whether proteostasis alteration facilitates prion protein misfolding or, rather, PrPSc protease resistance hampers cytoplasmic protein quality control. This review is aimed to critically analyze the most recent advancements in the cause-effect correlation between PrPC misfolding and proteostasis alterations and to discuss the possibility that pharmacological restoring of ubiquitin-proteasomal competence and stimulation of autophagy could reduce the intracellular burden of PrPSc and ameliorate the severity of prion-associated neurodegeneration.

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“…Besides, the connection between upregulation and/or accumulation of TRAF6 and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis (ALS) have been reported since TRAF6 triggers neuronal apoptosis and central nervous system (CNS) disruption. In CNS, TRAF6 also contributes to inflammatory responses in stroke and neuropathic pain [27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Structural Characterization of TRAF6 N-terminal for Therapeutic Uses

Güven

Çi̇ftçi̇

Tateishi

et al. 2023

Preprint

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Tumor Necrosis Factor Receptor Associated Factors (TRAFs) are a protein family with a wide variety of roles and binding partners. Among them, TRAF6, a ubiquitin ligase, possesses unique receptor binding specificity and shows diverse functions in immune system regulation, cellular signaling, central nervous system (CNS), and tumor formation. TRAF6 consists of an N-terminal Really Interesting New Gene (RING) domain, multiple zinc fingers, and a C-terminal TRAF domain. RING domain and zinc fingers mediate the activation of nuclear factor kappa B (NF-kB), which has essential roles in the regulation of inflammatory responses, proliferation, differentiation, migration, cell adhesion, and apoptosis. Therefore, it has been found that TRAF6 is overexpressed in various types of cancer including pancreatic, liver, lung, head and neck, breast, colorectal cancers, and melanoma along with inflammatory, autoimmune and neurodegenerative disorders. Furthermore, TRAF6 is an important therapeutic target for numerous disorders and structural studies of this protein are crucial for the development of next-generation therapeutics. Here, we present a TRAF6 N-terminal structure determined at the Turkish Light Source Turkish DeLight to 2.6 A; resolution at cryogenic temperature. This structure offers insight into the domain organization and zinc-binding, which are critical for protein function. Since the RING domain and the zinc fingers are key targets for TRAF6 therapeutics, structural insights are crucial for future research.

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The E3 Ubiquitin Ligase TRAF6 Interacts with the Cellular Prion Protein and Modulates Its Solubility and Recruitment to Cytoplasmic p62/SQSTM1-Positive Aggresome-Like Structures

Cited by 4 publications

References 66 publications

Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies

Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies

Proteostasis unbalance in prion diseases: Mechanisms of neurodegeneration and therapeutic targets

Structural Characterization of TRAF6 N-terminal for Therapeutic Uses

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