The Role of Torsin AAA+ Proteins in Preserving Nuclear Envelope Integrity and Safeguarding Against Disease

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.

Keywords: AAA+ ATPase; TorsinA; lipin; low-density lipoprotein (VLDL); nuclear pore complex (NPC).

Figure 1

Torsins are implicated in multiple essential cellular processes at the nuclear envelope (NE) and endoplasmic reticulum (ER). The ability of Torsins to participate in these diverse cellular activities relies upon their capacity to efficiently bind and hydrolyze ATP. This ATPase activity is mediated through an active site complementation mechanism in which one of two cofactors contributes a catalytic arginine residue to the active site. Shown is a side view of TorsinA (blue) complexed with the ER-specific cofactor luminal domain like LAP1 (LULL1) (red) (PDB: 5J1S) [12]. The TorsinA RecA fold composed of residues 55–221 is shown in dark blue and the C-terminal α-helical bundle (residues 272–332) is shown in light blue. The LULL1 luminal domain, residues 249–470, is represented in red.

Figure 2

(A) Mutations in TOR1A and TOR1AIP1 contribute to a variety of human disease pathologies. Shown is a comprehensive list of disease-associated mutations in the TOR1A (TorsinA) and TOR1AIP1 (lamina-associated polypeptide 1 or LAP1) genes. (B) Schematic representation of TorsinA and the LAP1 isoform LAP1B highlighting the alteration associated with the mutations from panel A. LAP1C is a shorter isoform of LAP1 that results from an alternative translation initiation site that ultimately leads to the absence of residues 1–121 [17]. All alterations, except for p.E62fsTer25 and p.Pro43fs*15 (red), are present in both isoforms. SS, signal sequence; H, hydrophobic region; WA, Walker A motif; WB, Walker B motif; TM, transmembrane helix.

Figure 3

Schematic representation of nuclear pore complex (NPC) biogenesis highlighting the two distinct assembly mechanisms. Post-mitotic insertion occurs during late mitosis where pre-existing NPC subcomplexes assemble at the reforming NE. Interphase assembly requires the de novo construction of NPCs into the double lipid bilayer of the NE. Upon Torsin manipulation, interphase assembly is stalled presumably prior to the fusion of the inner nuclear membrane (INM)/outer nuclear membrane (ONM). Note that cytoplasmic fibrils (CFs) containing NUP358 are only added to the nascent NPC after INM/ONM fusion during interphase assembly (i.e., the observed absence of NUP358 from blebs containing NPC components supports the idea of blebs representing stalled NPC assembly intermediates) [32,84].