Abstract
Torsin ATPases are members of the AAA+ (ATPases associated with various cellular activities) superfamily of proteins, which participate in essential cellular processes. While AAA+ proteins are ubiquitously expressed and demonstrate distinct subcellular localizations, Torsins are the only AAA+ to reside within the nuclear envelope (NE) and endoplasmic reticulum (ER) network. Moreover, due to the absence of integral catalytic features, Torsins require the NE- and ER-specific regulatory cofactors, lamina-associated polypeptide 1 (LAP1) and luminal domain like LAP1 (LULL1), to efficiently trigger their atypical mode of ATP hydrolysis. Despite their implication in an ever-growing list of diverse processes, the specific contributions of Torsin/cofactor assemblies in maintaining normal cellular physiology remain largely enigmatic. Resolving gaps in the functional and mechanistic principles of Torsins and their cofactors are of considerable medical importance, as aberrant Torsin behavior is the principal cause of the movement disorder DYT1 early-onset dystonia. In this review, we examine recent findings regarding the phenotypic consequences of compromised Torsin and cofactor activities. In particular, we focus on the molecular features underlying NE defects and the contributions of Torsins to nuclear pore complex biogenesis, as well as the growing implications of Torsins in cellular lipid metabolism. Additionally, we discuss how understanding Torsins may facilitate the study of essential but poorly understood processes at the NE and ER, and aid in the development of therapeutic strategies for dystonia.
Highlights
Over 20 years ago, researchers identified the mutation responsible for causing a severe neurological disorder called DYT1 dystonia, which is characterized by involuntary and prolonged muscle contractions [1]
These necessary protein cofactors are lamina-associated polypeptide 1 (LAP1), which localizes to the inner nuclear membrane (INM), and luminal domain like LAP1 (LULL1), which remains within the peripheral endoplasmic reticulum (ER) [5,9]
The findings discussed above demonstrate that significant progress has recently been made to determine the cellular roles of the mysterious family of Torsin ATPases
Summary
Over 20 years ago, researchers identified the mutation responsible for causing a severe neurological disorder called DYT1 (for torsion dystonia gene 1) dystonia, which is characterized by involuntary and prolonged muscle contractions [1]. Even more distinct is the situation in tissue culture cells, Biomolecules 2020, 10, 468 the situation in tissue culture cells, such as mouse embryonic fibroblasts (MEFs) or osteosarcoma (U2OS) cells, where TorsinA and TorsinB are expressed at nearly identical levels [18,19] These differences may account for the fact that the TorsinA∆E mutant affects neurons. Many distinct properties of Torsins produce a complicated system that has been reported to affect an ever-expanding number of cellular processes (Figure 1) Some of these diverse processes include lipid metabolism [21,22,23], nucleo-cytoskeleton coupling [24,25,26], membrane remodeling [13,27,28], ER redox monitoring [7,29], nuclear pore complex (NPC) biogenesis [30,31,32], and protein quality control [33,34,35,36,37] (Figure 1). We provide an update on Torsins’ oligomeric assembly and biochemistry, and their connection to human health and disease
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