[HTML][HTML] The role of torsin AAA+ proteins in preserving nuclear envelope integrity and safeguarding against disease

AJ Rampello, SM Prophet, C Schlieker - Biomolecules, 2020 - mdpi.com
AJ Rampello, SM Prophet, C Schlieker
Biomolecules, 2020mdpi.com
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 …
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.
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