LULL1 Retargets TorsinA to the Nuclear Envelope Revealing an Activity That Is Impaired by the<i>DYT1</i>Dystonia Mutation

Heyden, Abigail B. Vander; Naismith, Teresa V.; Snapp, Erik L.; Hodzic, Didier; Hanson, Phyllis I.

doi:10.1091/mbc.e09-01-0094

Cited by 115 publications

(178 citation statements)

References 49 publications

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“…On the other hand, overexpression of LAP1 and LULL1 recruits torsinA to the nuclear envelope [11,28]. A recent study reported that ATPase activity of torsinA is induced in the presence of LAP1 or LULL1 and that LAP1 and LULL1 are regulatory cofactors of torsinA [12].…”

Section: Discussionmentioning

confidence: 99%

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

Kayman-Kurekci

Talim

Korkusuz

et al. 2014

Neuromuscular Disorders

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We performed genome-wide homozygosity mapping and mapped a novel myopathic phenotype to chromosomal region 1q25 in a consanguineous family with three affected individuals manifesting proximal and distal weakness and atrophy, rigid spine and contractures of the proximal and distal interphalangeal hand joints. Additionally, cardiomyopathy and respiratory involvement were noted. DNA sequencing of torsinA-interacting protein 1 (TOR1AIP1) gene encoding lamina-associated polypeptide 1B (LAP1B), showed a homozygous c.186delG mutation that causes a frameshift resulting in a premature stop codon (p.E62fsTer25). We observed that expression of LAP1B was absent in the patient skeletal muscle fibres. Ultrastructural examination showed intact sarcomeric organization but alterations of the nuclear envelope including nuclear fragmentation, chromatin bleb formation and naked chromatin. LAP1B is a type-2 integral membrane protein localized in the inner nuclear membrane that binds to both A-and B-type lamins, and is involved in the regulation of torsinA ATPase. Interestingly, luminal domain-like LAP1 (LULL1)-an endoplasmic reticulum-localized partner of torsinA-was overexpressed in the patient's muscle in the absence of LAP1B. Therefore, the findings suggest that LAP1 and LULL1 might have a compensatory effect on each other. This study expands the spectrum of genes associated with nuclear envelopathies and highlights the critical function for LAP1B in striated muscle.

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Section: Discussionmentioning

confidence: 99%

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

Kayman-Kurekci

Talim

Korkusuz

et al. 2014

Neuromuscular Disorders

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“…Therefore, the impaired interaction between the ⌬E-torsinA and the lumenal domain of LAP1 (Fig. 5), probably as well as other NE proteins such as SUNs and nesprins (24,26), would explain the dystonia-associated disruption of the neuronal nuclear envelope (44,46) arising from the inability of LAP1 to maintain nuclear structure during neuronal maturation. LULL1 shares remarkable similarities with LAP1, suggesting that the N-terminal cytoplasmic domain of LULL1 may interact with some unknown molecules in the cytoplasm, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence suggests that torsinA may act on substrate(s) both in the nuclear envelope (NE) and in the ER (21,22). Two putative substrates have been identified: laminaassociated polypeptide 1 (LAP1) in the NE and lumenal domain like LAP1 (LULL1) in the ER (23)(24)(25). Consistent with the NE localization, torsinA has been reported to associate with outer nuclear membrane proteins, including SUNs (24) and nesprins (26) and some cytoskeletal components such as vimentin and actin (27), implicating its roles in NE structure regulation, cell adhesion, and neurite extension.…”

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confidence: 99%

“…Two putative substrates have been identified: laminaassociated polypeptide 1 (LAP1) in the NE and lumenal domain like LAP1 (LULL1) in the ER (23)(24)(25). Consistent with the NE localization, torsinA has been reported to associate with outer nuclear membrane proteins, including SUNs (24) and nesprins (26) and some cytoskeletal components such as vimentin and actin (27), implicating its roles in NE structure regulation, cell adhesion, and neurite extension. Although the interaction of torsinA with these binding partners was reported to be impaired by the DYT1 mutation (24 -26), the structural effect of the ⌬E deletion has not been determined, nor have its effects on the nucleotide and redox sensing functions of torsinA been elucidated.…”

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confidence: 99%

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A Unique Redox-sensing Sensor II Motif in TorsinA Plays a Critical Role in Nucleotide and Partner Binding

Zhu

Millen

Mendoza

et al. 2010

Journal of Biological Chemistry

113

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Early onset dystonia is commonly associated with the deletion of one of a pair of glutamate residues (⌬E302/303) near the C terminus of torsinA, a member of the AAA؉ protein family (ATPases associated with a variety of cellular activities) located in the endoplasmic reticulum lumen. The functional consequences of the disease-causing mutation, ⌬E, are not currently understood. By contrast to other AAA؉ proteins, torsin proteins contain two conserved cysteine residues in the C-terminal domain, one of which is located in the nucleotide sensor II motif. Depending on redox status, an ATP hydrolysis mutant of torsinA interacts with lamina-associated polypeptide 1 (LAP1) and lumenal domain like LAP1 (LULL1). Substitution of the cysteine in sensor II diminishes the redox-regulated interaction of torsinA with these substrates. Significantly, the dystonia-causing mutation, ⌬E, alters the ability of torsinA to mediate the redox-regulated interactions with LAP1 and LULL1. Limited proteolysis experiments reveal redox-and mutation-dependent changes in the local conformation of torsinA as a function of nucleotide binding. These results indicate that the cysteinecontaining sensor II plays a critical role in redox sensing and the nucleotide and partner binding functions of torsinA and suggest that loss of this function of torsinA contributes to the development of DYT1 dystonia.Torsion dystonia is an autosomal dominant movement disorder that causes the muscles to contract and spasm involuntarily. These muscle contractions force the body into repetitive movements and often twisted postures. The most common and severe early onset form of dystonia has been linked to the mutations in the human DYT1 (TOR1A) gene encoding the protein torsinA (1, 2). Although the function of torsinA and the mechanism underlying dystonia disease remain obscure, the sequence of torsinA is homologous to a large and diverse group of ATP-dependent oligomeric proteins named the AAAϩ protein family. The AAAϩ proteins typically form oligomeric rings that catalyze a variety of cellular processes, including protein translocation, membrane trafficking, and conformational remodeling of regulatory factors (3-5). TorsinA is the founding member of a subfamily of AAAϩ proteins that includes torsinB (TOR1B) and two other related gene products (TOR2A and TOR3A) in mammals and OOC-5 in Caenorhabditis elegans (1, 6, 7).The signal sequence and the following hydrophobic region at the N terminus (Fig. 1A) target torsinA to the lumen of the endoplasmic reticulum (ER). 3 In the ER, torsinA perhaps acts on secreted (8, 9) or stress-related protein substrates (10). Unlike ClpA and ClpB, torsinA lacks a substrate-binding domain or other functional region outside its ATPase domain (11). Experimental evidence suggests that torsinA mediates varied cellular activities, including protection from toxic cellular stress (12-15), trafficking of membrane-associated proteins (16), and synaptic vesicle recycling (17). In this regard, torsinA regulates trafficking of a G-protein-coupled recept...

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“…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)(16)(17).…”

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confidence: 99%

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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LULL1 Retargets TorsinA to the Nuclear Envelope Revealing an Activity That Is Impaired by theDYT1Dystonia Mutation

Cited by 115 publications

References 49 publications

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

A Unique Redox-sensing Sensor II Motif in TorsinA Plays a Critical Role in Nucleotide and Partner Binding

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

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