Torsins: not your typical AAA+ ATPases

Abstract

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.

Dissecting Torsin/cofactor function at the nuclear envelope: a genetic study

“…Four Torsins are encoded in the human genome: TorsinA (TorA), TorsinB (TorB), Torsin2A (Tor2A), and Torsin3A (Tor3A; Rose et al ., 2015; Laudermilch and Schlieker, 2016). Torsins are the only members of the AAA+ family that reside in the lumen of the endoplasmic reticulum (ER) and contiguous perinuclear space (PNS; Goodchild and Dauer, 2004, 2005; Vander Heyden et al ., 2009).…”

Emerging roles of the single EF-hand Ca2+ sensor tescalcin in the regulation of gene expression, cell growth and differentiation

“…At the mechanistic level, this broad range of biological functions involves protein phosphorylation, gene transcription, and protein degradation through cullin-RING-E3 ubiquitin ligases (Kato and Yoneda-Kato, 2009;Wei et al, 2008). More than 50 proteins have been shown to interact with CSN subunits, but there are only two binding partners of CSN4: torsinA (also known as torsin-1A) (Granata et al, 2011), a poorly understood ATPase known for its localization in endoplasmic reticulum and association with movement disorders (Rose et al, 2015) and tescalcin. Tescalcin specifically binds to CSN4 through its proteasomeCop9-eIF3 (PCI) domain in a Ca 2+ -dependent manner; this was shown by using purified recombinant proteins in a yeast two-hybrid system and a luciferase reporter assay in transfected HEK293 cells (Levay and Slepak, 2014).…”

A model for coordinating nuclear mechanics and membrane remodeling to support nuclear integrity

“…Interestingly, torsin alone does not function as an efficient ATPase; its active site is formed through binding to either the integral INM protein LAP1 or the ER membrane protein LULL1, making torsin a unique lumenal-targeted member of the AAA+ ATPase family that might have distinct substrates in different NE/ER subcompartments [70,71]. Significant effort is being directed towards identifying these substrates [72]; these will very likely include NE components, as depletion or mutation of torsin in some cell types leads to the accumulation of INM evaginations [17,18,73]. These data suggest that torsin might be involved with resolving INM-buds to form intralumenal vesicles in a mechanism that is required for mega-RNP egress [18], or perhaps even the removal of protein aggregates from the nuclear interior [74] (Fig.…”