Regulated protein turnover: snapshots of the proteasome in action

Bhattacharyya, Somnath; Yu, Houqing; Mim, Carsten; Matouschek, Andreas T

doi:10.1038/nrm3741

Cited by 225 publications

(228 citation statements)

References 179 publications

(258 reference statements)

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“…It is postulated that cleavage may cause conformational change of the TDP-43-C, which enables it for direct and quick access to the chamber of the 20S proteasome. 43 As TDP-43-C contains a portion of the glycinerich region that is required for its interaction with other hnRNPs, and for the regulation of alternative splicing and transcriptional activity, 12 we propose that rapid removal of TDP-43-C contributes to the loss-of-function of TDP-43 following CVB3 infection. In addition to loss-of-function, our results also suggest a gain-of-toxic-function for TDP-43-N. We demonstrated that expression of TDP-43-N in HeLa cells, which contain abundant endogenous TDP-43, results in a significant reduction of CFTR splicing, indicating that TDP-43-N inhibits the biological functions of native TDP-43 as a dominantnegative mutant.…”

Section: Discussionmentioning

confidence: 92%

Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis

et al. 2015

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We have previously demonstrated that infection by coxsackievirus B3 (CVB3), a positive-stranded RNA enterovirus, results in the accumulation of insoluble ubiquitin-protein aggregates, which resembles the common feature of neurodegenerative diseases. The importance of protein aggregation in viral pathogenesis has been recognized; however, the underlying regulatory mechanisms remain ill-defined. Transactive response DNA-binding protein-43 (TDP-43) is an RNA-binding protein that has an essential role in regulating RNA metabolism at multiple levels. Cleavage and cytoplasmic aggregation of TDP-43 serves as a major molecular marker for amyotrophic lateral sclerosis and frontotemporal lobar degeneration and contributes significantly to disease progression. In this study, we reported that TDP-43 is translocated from the nucleus to the cytoplasm during CVB3 infection through the activity of viral protease 2A, followed by the cleavage mediated by viral protease 3C. Cytoplasmic translocation of TDP-43 is accompanied by reduced solubility and increased formation of protein aggregates. The cleavage takes place at aminoacid 327 between glutamine and alanine, resulting in the generation of an N-and C-terminal cleavage fragment of~35 and~8 kDa, respectively. The C-terminal product of TDP-43 is unstable and quickly degraded through the proteasome degradation pathway, whereas the N-terminal truncation of TDP-43 acts as a dominant-negative mutant that inhibits the function of native TDP-43 in alternative RNA splicing. Lastly, we demonstrated that knockdown of TDP-43 results in an increase in viral titers, suggesting a protective role for TDP-43 in CVB3 infection. Taken together, our findings suggest a novel model by which cytoplasmic redistribution and cleavage of TDP-43 as a consequence of CVB3 infection disrupts the solubility and transcriptional activity of TDP-43. Our results also reveal a mechanism evolved by enteroviruses to support efficient viral infection. Coxsackievirus B3 (CVB3) is a small, positive-stranded RNA enterovirus. 1 The single open reading frame of CVB3 is translated into a viral polypeptide that is subsequently cleaved by two virus-encoded proteases 2A and 3C to generate structural and non-structural proteins. 2 In addition to processing viral polyprotein, 2A and 3C target host proteins important for maintenance of protein translation and transcription, antiviral activity, and cellular architecture and signaling, contributing to virus-induced pathogenesis. [3][4][5] Although enteroviral replication takes place exclusively in the cytoplasm, viral infection has been demonstrated to lead to cytoplasmic translocation of nuclear proteins. 6 For example, heterogeneous ribonucleoprotein D (hnRNP D) has been shown to translocate from the nucleus to the cytoplasm during enteroviral infection. 5,7,8 Moreover, hnRNP D is cleaved by 3C and has an antiviral function against enteroviral infection. 5,7,8 Cytoplasmic translocation after enteroviral infection has also been demonstrated for several other hnRNPs (A1, C, and K)...

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Section: Discussionmentioning

confidence: 92%

Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis

et al. 2015

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“…The 19S regulatory particle (~900 kDa) binds and unfolds the ubiquitinated substrates, and the 20S proteolytic core (~700 kDa) is responsible for the hydrolysis of the substrate proteins. 31,32 The 19S particle, attached at either or both ends of the 20S particle, consists of two sub-complexes, the base and the lid. The base is composed of six ATPases (regulatory particle triple A proteins RPT1-RPT6), two large organizing subunits (regulatory particle nonATPases 1 [RPN1] and 2 [RPN2]), and two ubiquitin receptors (RPN10 and RPN13).…”

Section: Congenital Malformationsmentioning

confidence: 99%

“…The base is composed of six ATPases (regulatory particle triple A proteins RPT1-RPT6), two large organizing subunits (regulatory particle nonATPases 1 [RPN1] and 2 [RPN2]), and two ubiquitin receptors (RPN10 and RPN13). 1,[31][32][33][34] The lid is formed from the deubiquitylating enzyme RPN11 and eight non-ATPase subunits (RPN3, RPN5-RPN9, RPN12, and RPN15), containing the PCI (proteasome-CSN [COP9 signalosome]-eIF3 [eukaryotic translation initiation factor 3]) domains. 1,[31][32][33][34] Whereas the base acts as a reverse chaperone, unfolding and translocating substrate proteins into the 20S cavity, the lid ensures substrate recognition, deubiquitination, and scaffolding.…”

Section: Congenital Malformationsmentioning

confidence: 99%

“…1,[31][32][33][34] The lid is formed from the deubiquitylating enzyme RPN11 and eight non-ATPase subunits (RPN3, RPN5-RPN9, RPN12, and RPN15), containing the PCI (proteasome-CSN [COP9 signalosome]-eIF3 [eukaryotic translation initiation factor 3]) domains. 1,[31][32][33][34] Whereas the base acts as a reverse chaperone, unfolding and translocating substrate proteins into the 20S cavity, the lid ensures substrate recognition, deubiquitination, and scaffolding. 1,31,32,35,36 All variants reported in the present case series involve PSMD12, which encodes PSMD12 (aka RPN5), one of the nine subunits of the 19S lid.…”

Section: Congenital Malformationsmentioning

confidence: 99%

“…1,[31][32][33][34] Whereas the base acts as a reverse chaperone, unfolding and translocating substrate proteins into the 20S cavity, the lid ensures substrate recognition, deubiquitination, and scaffolding. 1,31,32,35,36 All variants reported in the present case series involve PSMD12, which encodes PSMD12 (aka RPN5), one of the nine subunits of the 19S lid. We therefore speculated that the above functions of the 19S lid, and thereby those of the 26S proteasome, would be substantially altered in the described subjects.…”

Section: Congenital Malformationsmentioning

confidence: 99%

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De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Küry¹,

Besnard²,

Ebstein³

et al. 2017

The American Journal of Human Genetics

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Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.Proteolysis by the ubiquitin-proteasome system (UPS) is a tightly regulated biological process in eukaryotic cells and is crucial for their homeostasis, signaling, and fate determination. 1-3 Proteins subjected to degradation are typically marked by polyubiquitin chains to be hydrolyzed in a precise, rapid, timely, and ATP-dependent manner by the 19S regulatory subunit of the 26S proteasome. 3-6 UPS-dependent degradation essentially contributes to proteostasis and plays a key role in neuronal development and function 7,8 by regulating synaptic plasticity, 9,10

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PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features

Khalil

Kenny

Hill

et al. 2018

American J of Med Genetics Pt B

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Protein homeostasis is tightly regulated by the ubiquitin proteasome pathway. Disruption of this pathway gives rise to a host of neurological disorders. Through whole exome sequencing (WES) in families with neurodevelopmental disorders, we identified mutations in PSMD12, a core component of the proteasome, underlying a neurodevelopmental disorder with intellectual disability (ID) and features of autism spectrum disorder (ASD). We performed WES on six affected siblings from a multiplex family with ID and autistic features, the affected father, and two unaffected mothers, and a trio from a simplex family with one affected child with ID and periventricular nodular heterotopia. We identified an inherited heterozygous nonsense mutation in PSMD12 (NM_002816: c.367C>T: p.R123X) in the multiplex family and a de novo nonsense mutation in the same gene (NM_002816: c.601C>T: p.R201X) in the simplex family. PSMD12 encodes a non-ATPase regulatory subunit of the 26S proteasome. We confirm the association of PSMD12 with ID, present the first cases of inherited PSMD12 mutation, and demonstrate the heterogeneity of phenotypes associated with PSMD12 mutations.

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Regulated protein turnover: snapshots of the proteasome in action

Cited by 225 publications

References 179 publications

Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis

Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features

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