Torsin ATPases (Torsins) belong to the widespread AAA+ (ATPases associated with a variety of cellular activities) family of ATPases, which share structural similarity but have diverse cellular functions. Torsins are outliers in this family because they lack many characteristics of typical AAA+ proteins, and they are the only members of the AAA+ family located in the endoplasmic reticulum and contiguous perinuclear space. While it is clear that Torsins have essential roles in many, if not all metazoans, their precise cellular functions remain elusive. Studying Torsins has significant medical relevance since mutations in Torsins or Torsin-associated proteins result in a variety of congenital human disorders, the most frequent of which is Early Onset Torsion (DYT1) Dystonia, a severe movement disorder. A better understanding of the Torsin system is needed to define the molecular etiology of these diseases, potentially enabling corrective therapy. Here, we provide a comprehensive overview of the Torsin system in metazoans, discuss functional clues obtained from various model systems and organisms, and provide a phylogenetic and structural analysis of Torsins and their regulatory cofactors in relation to disease-causative mutations. Moreover, we review recent data that has led to a dramatically improved understanding of these machines at a molecular level, providing a foundation for investigating the molecular defects underlying the associated movement disorders. Lastly, we discuss our ideas on how recent progress may be utilized to inform future studies aimed at determining the cellular role(s) of these atypical molecular machines and their implications for dystonia treatment options.

Background:TorsinB is an AAAϩ ATPase of unknown function. Results: ATPase-arrested TorsinB induces the formation of LULL1-enriched, luminally constricted ER membranes requiring a highly conserved C-terminal motif in TorsinB. Conclusion: Membrane structures formed by the TorsinB dominant-negative mutant are dependent on association with ATPase-activating factor LULL1. Significance: This study supports a role for TorsinB in membrane dynamics.

Herpesvirus capsids traverse the nuclear envelope by utilizing an unusual export pathway termed nuclear egress. In this process, the viral capsid is delivered into the perinuclear space, producing a vesicular intermediate after fission. After fusion with the outer nuclear membrane, the naked capsid is released into the cytosol. A recent study now suggests that this pathway might be an endogenous cellular pathway, co-opted by viruses, that serves to transport cellular cargo exceeding the size limit imposed by the nuclear pore complex. We propose that one function of this pathway is to transport nuclear protein aggregates to the cytosolic autophagy machinery. Our model has implications for our understanding of laminopathies and related diseases affecting proteins residing at the inner nuclear membrane and nuclear lamina.

Strand transfer drives recombination between the co-packaged genomes of HIV-1, a process that allows rapid viral evolution. The proposed invasion-mediated mechanism of strand transfer during HIV-1 reverse transcription has three steps: invasion of the initial or donor primer-template by the second or acceptor template, propagation of the primer-acceptor hybrid, and then primer terminus transfer. Invasion occurs at a site at which the RT RNase has created a nick or short gap in the donor template. We used biochemical reconstitution to determine the distance over which a single invasion site can promote transfer. The DNA-primed RNA donor template used had a single stranded precreated invasion site (PCIS). Results showed that the PCIS could influence transfer twenty or more nucleotides in the direction of synthesis. This influence was augmented by viral nucleocapsid protein (NC) and additional reverse transcriptase (RT) ribonuclease H (RNase H) cleavage. Strand exchange assays were performed specifically to assess the distance over which a hybrid interaction initiated at the PCIS could propagate to achieve transfer. Propagation by simple branch migration of strands was limited to 24 – 32 nucleotides. Additional RNase H cuts in the donor RNA allowed propagation to a maximum distance of 32 – 64 nucleotides. Overall, results indicate that a specific invasion site has a limited range of influence on strand transfer. Evidently, a series of invasion sites cannot collaborate over a long distance to promote transfer. This result explains why the frequency of recombination events does not increase with increasing distance from the start of synthesis, a characteristic that supports effective mixing of viral mutations.