The UBL domain of PLIC‐1 regulates aggresome formation

Heir, Renu; Ablasou, Celine; Dumontier, Émilie; Elliott, Meghan J.; Fagotto‐Kaufmann, Christine; Bedford, Fiona K.

doi:10.1038/sj.embor.7400823

Cited by 81 publications

(103 citation statements)

References 29 publications

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“…Specifically, ubiquilin has been shown to protect against polyglutamine-induced toxicity in cellular and invertebrate models of Huntington's disease (60,61). Ubiquilin is also involved in aggresome formation (62) and may promote removal of cellular aggregates via autophagy (63,64). Taken together, our results and those from previous studies suggest that ubiquilin plays an important role in quality control of aggregation-prone cellular proteins.…”

Section: Ubiquilin-1 Is a Molecular Chaperonesupporting

confidence: 79%

Ubiquilin-1 Is a Molecular Chaperone for the Amyloid Precursor Protein

Stieren

Ayadi

Xiao

et al. 2011

Journal of Biological Chemistry

109

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Alzheimer disease (AD) is associated with extracellular deposition of proteolytic fragments of amyloid precursor protein (APP). Although mutations in APP and proteases that mediate its processing are known to result in familial, early onset forms of AD, the mechanisms underlying the more common sporadic, yet genetically complex forms of the disease are still unclear. Four single-nucleotide polymorphisms within the ubiquilin-1 gene have been shown to be genetically associated with AD, implicating its gene product in the pathogenesis of late onset AD. However, genetic linkage between ubiquilin-1 and AD has not been confirmed in studies examining different populations. Here we show that regardless of genotype, ubiquilin-1 protein levels are significantly decreased in late onset AD patient brains, suggesting that diminished ubiquilin function may be a common denominator in AD progression. Our interrogation of putative ubiquilin-1 activities based on sequence similarities to proteins involved in cellular quality control showed that ubiquilin-1 can be biochemically defined as a bona fide molecular chaperone and that this activity is capable of preventing the aggregation of amyloid precursor protein both in vitro and in live neurons. Furthermore, we show that reduced activity of ubiquilin-1 results in augmented production of pathogenic amyloid precursor protein fragments as well as increased neuronal death. Our results support the notion that ubiquilin-1 chaperone activity is necessary to regulate the production of APP and its fragments and that diminished ubiquilin-1 levels may contribute to AD pathogenesis.

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Section: Ubiquilin-1 Is a Molecular Chaperonesupporting

confidence: 79%

Ubiquilin-1 Is a Molecular Chaperone for the Amyloid Precursor Protein

Stieren

Ayadi

Xiao

et al. 2011

Journal of Biological Chemistry

109

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“…Previous studies demonstrated that UBQLN forms aggresome-like structures when coexpressed with presenilins or polyglutamine proteins and that UBQLN colocalizes with endosomal and proteasomal markers (34,35,52,53). UBQLN interacts with the S5a subunit of the 19 S proteasome cap in a UBL domain-dependent manner (53,54) and its overexpression results in the accumulation of several proteins, including GABA A , PS1/PS2, p53, amyloid precursor protein, IB␣, and Kaposi sarcoma-associated Herpesvirus protein K7 (52,(55)(56)(57)(58). A general model that has emerged from these studies is that UBQLN and related UBL-UBA domain proteins, such as RAD23, regulate protein homeostasis by guiding ubiquitylated substrates to the proteasome via UBA-polyubiquitin interactions (29,34,36,51).…”

Section: Discussionmentioning

confidence: 99%

Potentiation of Amyotrophic Lateral Sclerosis (ALS)-associated TDP-43 Aggregation by the Proteasome-targeting Factor, Ubiquilin 1

Kim¹,

Shi²,

Hanson³

et al. 2009

Journal of Biological Chemistry

107

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Amyotrophic lateral sclerosis (ALS)5 is a progressive, typically fatal, neurodegenerative disease that targets motor neurons (1). The cumulative lifetime risk for ALS is ϳ1 in 1000, which is comparable with the occurrence rate of multiple sclerosis (1). However, only about 3,000 cases of ALS are observed at any given time in the United States, because of the low fiveyear median survival rate (20%) for this disease. There are currently no effective treatments to halt the course of ALS.Approximately 10% of ALS cases, termed familial ALS (fALS), have a clear genetic link. Dominant mutations in the Cu,Zn-superoxide dismutase 1 (SOD1) are responsible for ϳ20% of fALS (2). Well over 100 different disease-associated mutations in SOD1 have been identified in humans (3). The mutations occur throughout the SOD1 open reading frame and do not alter the catalytic properties of the SOD1 enzyme per se (4). Instead, mutant SOD1 proteins are thought to acquire an abnormal fold that confers a toxic gain-of-function activity (4). Multiple cellular processes, including mitochondrial function, axon transport, and glutamate transporter function are adversely affected by toxic SOD1 mutants (5-10). Remarkably, mouse models of SOD1-induced ALS have shown that it is not a neuron-autonomous disease; expression of toxic SOD1 mutants in non-neuronal glial cells is sufficient to induce neuron pathology, whereas expression of toxic SOD1 mutants in motor neurons is insufficient for full expression of the disease phenotype (11,12). The SOD1 mouse model has been used to test candidate ALS therapeutics, including gene therapies directed toward silencing toxic SOD1 alleles in fALS (13)(14)(15).Sporadic ALS (sALS), representing 90 -95% of all ALS cases, occurs in the absence of a family history of disease, but follows a clinical course that is similar to SOD1 ALS. A hallmark of sALS is the presence of ubiquitin (Ub)-positive cytosolic aggregates in degenerating motor neurons (16). Recently, Neumann et al. (17) demonstrated that the 43-kDa human immunodeficiency virus transactivating region DNA-binding domain protein (TDP-43) is a major protein component of ubiquitin-positive aggregates in patients with sALS or ubiquitin-positive fronto-temporal lobular dementia. First identified as a binding factor of the long-terminal repeat region of the human immunodeficiency virus genome, TDP-43 is a nuclear RNA-binding protein that regulates splicing of the cystic fibrosis transmembrane conductance regulator mRNA (18 -20). Inactivation of TDP-43 through RNA interference caused enhanced transcription of cyclin-dependent kinase 6, hyperphosphorylation of the

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“…Aggresomes are induced by various proteins such as ␣-synuclein (Lee and Lee, 2002) and HDAC6 deacetylase in Parkinson's disease (Kawaguchi et al, 2003) and prions in prion-associated disease (Kristiansen et al, 2005). Smaller scattered protein aggregates or aggresome-like structures are detected, for example, with PLIC-1 (Heir et al, 2006) and p62/SQSTM1 (Zatloukal et al, 2002;Paine et al, 2005;Pankiv et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Prolyl Hydroxylase PHD3 Activates Oxygen-dependent Protein Aggregation

Rantanen

Pursiheimo

Högel

et al. 2008

MBoC

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The HIF prolyl hydroxylases (PHDs/EGLNs) are central regulators of the molecular responses to oxygen availability. One isoform, PHD3, is expressed in response to hypoxia and causes apoptosis in oxygenated conditions in neural cells. Here we show that PHD3 forms subcellular aggregates in an oxygen-dependent manner. The aggregation of PHD3 was seen under normoxia and was strongly reduced under hypoxia or by the inactivation of the PHD3 hydroxylase activity. The PHD3 aggregates were dependent on microtubular integrity and contained components of the 26S proteasome, chaperones, and ubiquitin, thus demonstrating features that are characteristic for aggresome-like structures. Forced expression of the active PHD3 induced the aggregation of proteasomal components and activated apoptosis under normoxia in HeLa cells. The apoptosis was seen in cells prone to PHD3 aggregation and the PHD3 aggregation preceded apoptosis. The data demonstrates the cellular oxygen sensor PHD3 as a regulator of protein aggregation in response to varying oxygen availability. INTRODUCTIONHypoxia forms a key component of multiple diseases, including stroke, inflammatory diseases and the progression of solid tumors. Hypoxia and in some cases the following reoxygenation pose considerable stress to cells. These include increased production of reactive oxygen species (ROS) and changes in protein translation, as well as exposure of cells to protein damage and misfolding (Rifkind et al., 1991;Koumenis and Wouters, 2006;Liu et al., 2006;Thuerauf et al., 2006). Mammalian cells have evolved a molecular machinery to determine whether cells attempt to survive or go into apoptosis in these conditions. The best characterized molecular responses to hypoxia are mediated through a family of dioxygenases that use O 2 as a cosubstrate (Bruick and McKnight, 2001;Epstein et al., 2001) and are termed prolyl hydroxylase domain proteins (PHD), also known as HIF prolyl hydroxylases or Egl-9 homologues (EGLN). Three known PHD (PHD1-3) isoforms hydroxylate the ␣-subunits of hypoxia-inducible factors 1 and 2 (HIF-1 and -2) under normoxic conditions at two proline residues (Pro402 and 564; Ivan et al., 2001;Jaakkola et al., 2001;Yu et al., 2001;Masson et al., 2004). The hydroxylated HIF-1␣ is recognized by the von Hippel-Lindau tumor suppressor protein (pVHL) that subsequently leads to ubiquitination and proteosomal destruction of HIF-1␣ (Kallio et al., 1999;Maxwell et al., 1999;Cockman et al., 2000;Ohh et al., 2000;Tanimoto et al., 2000). Under restricted O 2 availability the PHD activity decreases and the degradation of HIF-1␣ is blocked, activating the transcription of a wide range of genes (Semenza, 2001;Harris, 2002;Pugh and Ratcliffe, 2003;Schofield and Ratcliffe, 2004).All PHD isoforms have been reported to hydroxylate HIF and to have similar requirements for O 2 and cosubstrates FeII and 2-oxoglutarate at least in vitro (Hirsila et al., 2003). However, their function and characteristics also differ in several aspects. Two isoforms, PHD2 and PHD3, are upregulated tra...

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The UBL domain of PLIC‐1 regulates aggresome formation

Cited by 81 publications

References 29 publications

Ubiquilin-1 Is a Molecular Chaperone for the Amyloid Precursor Protein

Ubiquilin-1 Is a Molecular Chaperone for the Amyloid Precursor Protein

Potentiation of Amyotrophic Lateral Sclerosis (ALS)-associated TDP-43 Aggregation by the Proteasome-targeting Factor, Ubiquilin 1

Prolyl Hydroxylase PHD3 Activates Oxygen-dependent Protein Aggregation

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