Parkinson's Disease DJ-1 L166P Alters rRNA Biogenesis by Exclusion of TTRAP from the Nucleolus and Sequestration into Cytoplasmic Aggregates via TRAF6

Vilotti, Sandra; Codrich, Marta; Ferro, Marco Dal; Pinto, Milena; Ferrer, Isidró; Collavin, Licio; Gustincich, Stefano; Zucchelli, S.

doi:10.1371/journal.pone.0035051

Cited by 51 publications

(39 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown in Fig. 3A, TRAF6 in mock-infected cells displayed a diffused staining pattern in the whole cell, in agreement with the previous reports (27,28). Few autophagic vacuoles (i.e., GFP-LC3 puncta) could be detected in mock-infected cells.…”

Section: Suppression Of Traf6 Expression By Hcvsupporting

confidence: 92%

Suppression of Host Innate Immune Response by Hepatitis C Virus via Induction of Autophagic Degradation of TRAF6

Chan

Lee

Narula

et al. 2016

J Virol

View full text Add to dashboard Cite

Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an important adaptor molecule that mediates the TNFR family and interleukin-1 (IL-1)/Toll-like receptor (TLR) signaling cascades. These pathways are important for the host to control viral infections. In this report, we demonstrated that hepatitis C virus (HCV) depleted TRAF6 from its host cells through a posttranslational mechanism. This depletion was independent of proteasomes, as it was not affected by the proteasome inhibitor MG132, but it was suppressed by bafilomycin A1, which led to the association of TRAF6 with autophagosomes. As bafilomycin A1 is a vacuolar ATPase inhibitor that inhibits autophagic protein degradation, these results suggested that HCV depleted TRAF6 via autophagy. The degradation of TRAF6 was apparently mediated by the p62 sequestosome protein, which is a factor important for selective autophagy, as it could bind to TRAF6 and its silencing stabilized TRAF6. The depletion of TRAF6 suppressed activation of NF-B and induction of proinflammatory cytokines and enhanced HCV replication. In contrast, the overexpression of TRAF6 suppressed HCV replication. These results revealed a novel mechanism that was used by HCV to disrupt the host innate immune responses for viral replication and persistence. IMPORTANCEHCV can cause severe liver diseases and is one of the most important human pathogens. It establishes chronic infections in the great majority of patients that it infects, indicating that it has evolved sophisticated mechanisms to evade host immunity. TRAF6 is an important signaling molecule that mediates activation of NF-B and expression of proinflammatory cytokines and interferons. In this study, we found that HCV infection suppressed the host innate immune response through the induction of autophagic degradation of TRAF6. This finding provided important information for further understanding how HCV evades host immunity to establish persistence.

show abstract

Section: Suppression Of Traf6 Expression By Hcvsupporting

confidence: 92%

Suppression of Host Innate Immune Response by Hepatitis C Virus via Induction of Autophagic Degradation of TRAF6

Chan

Lee

Narula

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…The PDassociated L166P mutation of DJ-1 results in misfolding of the protein and its subsequent degradation. DJ-1(L166P) may also accumulate as insoluble aggregates under conditions of impaired proteasome function, resulting in activation of JNK and p38 MAPK pathways through interaction of the aggregates with TTRAP (TRAF-and TNF receptorassociated protein) as well as in the induction of apoptosis (Vilotti et al 2012).…”

Section: Parkinson's Diseasementioning

confidence: 99%

Compromised MAPK signaling in human diseases: an update

2015

View full text Add to dashboard Cite

The mitogen-activated protein kinases (MAPKs) in mammals include c-Jun NH2-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK). These enzymes are serine-threonine protein kinases that regulate various cellular activities including proliferation, differentiation, apoptosis or survival, inflammation, and innate immunity. The compromised MAPK signaling pathways contribute to the pathology of diverse human diseases including cancer and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The JNK and p38 MAPK signaling pathways are activated by various types of cellular stress such as oxidative, genotoxic, and osmotic stress as well as by proinflammatory cytokines such as tumor necrosis factor-α and interleukin 1β. The Ras-Raf-MEK-ERK signaling pathway plays a key role in cancer development through the stimulation of cell proliferation and metastasis. The p38 MAPK pathway contributes to neuroinflammation mediated by glial cells including microglia and astrocytes, and it has also been associated with anticancer drug resistance in colon and liver cancer. We here summarize recent research on the roles of MAPK signaling pathways in human diseases, with a focus on cancer and neurodegenerative conditions.

show abstract

“…The mutation causes DJ-1 to mis-fold resulting in either proteasomal degradation of DJ-1 or its accumulation in cytoplasmic Lewy Bodies that are typical within brain neurons of Parkinson patients. Formation of the cytoplasmic aggregates correlates with the redistribution of the tumor necrosis factor (TNF) receptor associated protein (TTRAP) from the nucleolus to these cytoplasmic granules 190 . Huntington disease also presents problems for nucleoli.…”

Section: Endogenous Mutations: the Ribosomopathiesmentioning

confidence: 99%

Nucleolar stress with and without p53

James

Wang

Raje

et al. 2014

Nucleus

237

280

View full text Add to dashboard Cite

A veritable explosion of primary research papers within the past 10 years focuses on nucleolar and ribosomal stress, and for good reason: with ribosome biosynthesis consuming ~80% of a cell’s energy, nearly all metabolic and signaling pathways lead ultimately to or from the nucleolus. We begin by describing p53 activation upon nucleolar stress resulting in cell cycle arrest or apoptosis. The significance of this mechanism cannot be understated, as oncologists are now inducing nucleolar stress strategically in cancer cells as a potential anti-cancer therapy. We also summarize the human ribosomopathies, syndromes in which ribosome biogenesis or function are impaired leading to birth defects or bone narrow failures; the perplexing problem in the ribosomopathies is why only certain cells are affected despite the fact that the causative mutation is systemic. We then describe p53-independent nucleolar stress, first in yeast which lacks p53, and then in other model metazoans that lack MDM2, the critical E3 ubiquitin ligase that normally inactivates p53. Do these presumably ancient p53-independent nucleolar stress pathways remain latent in human cells? If they still exist, can we use them to target >50% of known human cancers that lack functional p53?

show abstract

Parkinson's Disease DJ-1 L166P Alters rRNA Biogenesis by Exclusion of TTRAP from the Nucleolus and Sequestration into Cytoplasmic Aggregates via TRAF6

Cited by 51 publications

References 44 publications

Suppression of Host Innate Immune Response by Hepatitis C Virus via Induction of Autophagic Degradation of TRAF6

Suppression of Host Innate Immune Response by Hepatitis C Virus via Induction of Autophagic Degradation of TRAF6

Compromised MAPK signaling in human diseases: an update

Nucleolar stress with and without p53

Contact Info

Product

Resources

About