TorsinA – unlocking the mysteries of an AAA+ ATPase in the endoplasmic reticulum and nuclear envelope

Abstract

TorsinA is an AAA+ ATPase in the endoplasmic reticulum (ER) and nuclear envelope (NE) lumen that is mutated in dominantly inherited early onset DYT1 dystonia. TorsinA is an essential protein in mice, but its cellular function and the basis for disease are not well understood. We have previously shown that localization and activity of torsinA within the ER and NE are dynamically regulated by an interacting transmembrane protein, LULL1 (TOR1AIP2). To understand how torsinA responds to LULL1, we now identify features in both proteins responsible for controlling torsinA localization. We find that distinct regions mediate binding and torsinA re‐targeting, and establish among other things that the extreme N‐terminus of LULL1 must be present for torsinA to be directed to the NE. The N‐terminus of LULL1 is cytosolic, while its torsinA‐binding domain is lumenal, raising the intriguing possibility that control of torsinA localization involves communication between the cytosol and the ER lumen. When retargeted to the NE, torsinA displaces a subset of linker of the nucleoskeleton and cytoskeleton (LINC) complex proteins and may thereby modify NE structure and nuclear positioning. The disease causative torsinA mutant also responds to LULL1, but only weakly displaces LINC proteins.These findings identify a mechanism for regulating torsinA localization and activity via LULL1, and suggest that activity at the NE is perturbed by the disease‐causative mutation. Changes in torsinA activity at the NE may contribute to DYT1 dystonia.