Relative tissue expression of homologous torsinB correlates with the neuronal specific importance of DYT1 dystonia-associated torsinA

Jungwirth, Michael; Dear, Mary Lynn; Brown, P. S.; Holbrook, Kristen; Goodchild, Rose

doi:10.1093/hmg/ddp557

Cited by 82 publications

(141 citation statements)

References 47 publications

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“…Next, we confirmed the previous observation of a second TorA isoform in liver extracts (37,38). Based on our observation that this isoform co-migrates with TorAp on SDS-PAGE gels (Fig.…”

Section: -Nitroisatin Is a Cell-permeable Inhibitor Useful For Intersupporting

confidence: 91%

“…Of note, TorAp has an electrophoretic behavior indistinguishable from the TorA isoforms in liver (Fig. 7C) (37,38), again suggesting in vivo relevance of our observations. Because potent inducers of ER stress (with the exception of DTT) do not induce Torsin processing (Figs.…”

Section: Discussionsupporting

confidence: 72%

“…Finally, we wanted to investigate if previously observed, shorter TorA isoforms in organ isolates (37,38) correspond to TorAp, which would further support the idea that Torsin processing is physiologically relevant and occurs in authentic tissues. To this end, we prepared tissue homogenates from spleen, lymph nodes, and liver, and subjected the resulting detergent extracts to SDS-PAGE and immunoblotting.…”

Section: -Nitroisatin Is a Cell-permeable Inhibitor Useful For Intermentioning

confidence: 96%

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Site-specific Proteolysis Mobilizes TorsinA from the Membrane of the Endoplasmic Reticulum (ER) in Response to ER Stress and B Cell Stimulation

Zhao

Brown

Tang

et al. 2016

Journal of Biological Chemistry

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Torsin ATPases are the only representatives of the AAA؉ ATPase family that reside in the lumen of the endoplasmic reticulum (ER) and nuclear envelope. Two of these, TorsinA and TorsinB, are anchored to the ER membrane by virtue of an N-terminal hydrophobic domain. Here we demonstrate that the imposition of ER stress leads to a proteolytic cleavage event that selectively removes the hydrophobic domain from the AAA؉ domain of TorsinA, which retains catalytic activity. Both the pharmacological inhibition profile and the identified cleavage site between two juxtaposed cysteine residues are distinct from those of presently known proteases, suggesting that a hitherto uncharacterized, membrane-associated protease accounts for TorsinA processing. This processing occurs not only in stressexposed cell lines but also in primary cells from distinct organisms including stimulated B cells, indicating that Torsin conversion in response to physiologically relevant stimuli is an evolutionarily conserved process. By establishing 5-nitroisatin as a cell-permeable inhibitor for Torsin processing, we provide the methodological framework for interfering with Torsin processing in a wide range of primary cells without the need for genetic manipulation.The human genome encodes four Torsin ATPases (TorsinA, TorsinB, Torsin 2A, and Torsin3A), all of which are members of the ATPases associated with a variety of cellular activities (AAAϩ) 3 family (1, 2). Of those, TorsinA is the best characterized Torsin ATPase due to its association with the congenital movement disorder DYT1 dystonia (3). TorsinA has been implicated in a variety of cellular processes, including protein quality control and cellular stress responses (4 -9), although its precise mechanistic functions remain to be identified (2, 10). Although Torsins are phylogenetically closely related to Clp/ HSP100 proteins, they are characterized by a number of atypical features (for a recent review, see Refs. 2 and 10). On the primary structural level, these include differences in the Walker A motif responsible for nucleotide binding, as well as the absence of an otherwise conserved arginine residue required for ATP hydrolysis (10).TorsinA is directed to the lumen of the endoplasmic reticulum by a cleavable N-terminal signal sequence, which is followed by a hydrophobic domain responsible for membrane anchoring and ER retention (11). TorsinA is partitioned between the ER and the contiguous perinuclear space of the nuclear envelope, and its localization is controlled in part by its association with LAP1 and LULL1, type II transmembrane proteins residing in the nuclear envelope and ER, respectively (12)(13)(14). Another unusual property of Torsins is that they lack significant basal ATPase activity in isolation and are tightly regulated by LAP1 and LULL1, which integrate into the Torsin ring via AAA-like domains to trigger ATP hydrolysis through an active site complementation mechanism (15-17). Thus, Torsins and their ATPase activating cofactors form a composite, membrane-spanning assembly....

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“…Next, we confirmed the previous observation of a second TorA isoform in liver extracts (37,38). Based on our observation that this isoform co-migrates with TorAp on SDS-PAGE gels (Fig.…”

Section: -Nitroisatin Is a Cell-permeable Inhibitor Useful For Intersupporting

confidence: 91%

Section: Discussionsupporting

confidence: 72%

Section: -Nitroisatin Is a Cell-permeable Inhibitor Useful For Intermentioning

confidence: 96%

See 1 more Smart Citation

Site-specific Proteolysis Mobilizes TorsinA from the Membrane of the Endoplasmic Reticulum (ER) in Response to ER Stress and B Cell Stimulation

Zhao

Brown

Tang

et al. 2016

Journal of Biological Chemistry

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Section: A Dyt1: Early-onset Torsion Dystoniamentioning

confidence: 99%

“…The torsin family is comprised of four torsin genes in mammals consisting of torsinA, torsinB, torsin2, and torsin3, with several orthologs found in metazoans including zebrafish, C. elegans and D. melanogaster [65][66][67]. Sequence alignment revealed that all four mammalian torsin proteins contain an endoplasmic reticulum (ER) signal sequence and AAA+ domain and are localized to the ER lumen and nuclear envelope (NE) [67]. Although torsinB may be functionally similar, only torsinA exhibits high expression in neurons throughout the mammalian brain with subcellular localization extending from the ER and NE, to the cytoplasm and neuronal processes; this is suggestive of a neuronal specificity for torsinA expression that corresponds with its significance in EOTD [67][68][69].…”

Section: A Dyt1: Early-onset Torsion Dystoniamentioning

confidence: 99%

Invertebrate Models of Dystonia

Caldwell¹,

Shu²,

Roberts³

et al. 2013

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Abstract:The neurological movement disorder dystonia is an umbrella term for a heterogeneous group of related conditions where at least 20 monogenic forms have been identified. Despite the substantial advances resulting from the identification of these loci, the function of many DYT gene products remains unclear. Comparative genomics using simple animal models to examine the evolutionarily conserved functional relationships with monogenic dystonias represents a rapid route toward a comprehensive understanding of these movement disorders. Current studies using the invertebrate animal models Caenorhabditis elegans and Drosophila melanogaster are uncovering cellular functions and mechanisms associated with mutant forms of the well-conserved gene products corresponding to DYT1, DYT5a, DYT5b, and DYT12 dystonias. Here we review recent findings from the invertebrate literature pertaining to molecular mechanisms of these gene products, torsinA, GTP cyclohydrolase I, tyrosine hydroxylase, and the alpha subunit of Na+/K ATPase, respectively. In each study, the application of powerful genetic tools developed over decades of intensive work with both of these invertebrate systems has led to mechanistic insights into these human disorders. These models are particularly amenable to large-scale genetic screens for modifiers or additional alleles, which are bolstering our understanding of the molecular functions associated with these gene products. Moreover, the use of invertebrate models for the evaluation of DYT genetic loci and their genetic interaction networks has predictive value and can provide a path forward for therapeutic intervention.

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Coordinating nucleoporin condensation and nuclear pore complex assembly

Kuiper,

Prophet,

Schlieker

2023

FEBS Letters

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The nuclear pore complex (NPC) is among the most elaborate protein complexes in eukaryotes. While ribosomes and proteasomes are known to require dedicated assembly machinery, our understanding of NPC assembly is at a relatively early stage. Defects in NPC assembly or homeostasis are tied to movement disorders, including dystonia and amyotrophic lateral sclerosis (ALS), as well as aging, requiring a better understanding of these processes to enable therapeutic intervention. Here, we discuss recent progress in the understanding of NPC assembly and highlight how related defects in human disorders can shed light on NPC biogenesis. We propose that the condensation of phenylalanine‐glycine repeat nucleoporins needs to be carefully controlled during NPC assembly to prevent aberrant condensation, aggregation, or amyloid formation.

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Relative tissue expression of homologous torsinB correlates with the neuronal specific importance of DYT1 dystonia-associated torsinA

Cited by 82 publications

References 47 publications

Site-specific Proteolysis Mobilizes TorsinA from the Membrane of the Endoplasmic Reticulum (ER) in Response to ER Stress and B Cell Stimulation

Site-specific Proteolysis Mobilizes TorsinA from the Membrane of the Endoplasmic Reticulum (ER) in Response to ER Stress and B Cell Stimulation

Invertebrate Models of Dystonia

Coordinating nucleoporin condensation and nuclear pore complex assembly

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