Abstract
Torsins are membrane-tethered AAA+ ATPases residing in the nuclear envelope (NE) and endoplasmic reticulum (ER). Here, we show that the induction of a conditional, dominant-negative TorsinB variant provokes a profound reorganization of the endomembrane system into foci containing double membrane structures that are derived from the ER. These double-membrane sinusoidal structures are formed by compressing the ER lumen to a constant width of 15 nm, and are highly enriched in the ATPase activator LULL1. Further, we define an important role for a highly conserved aromatic motif at the C terminus of Torsins. Mutations in this motif perturb LULL1 binding, reduce ATPase activity, and profoundly limit the induction of sinusoidal structures.
Highlights
TorsinB is an AAAϩ ATPase of unknown function
This mutation leads to perinuclear inclusions in the cell [3,4,5,6,7], and strongly compromises TorA binding to lamina-associated polypeptide 1 (LAP1) and the related protein LULL1 [8, 9], which are type II transmembrane proteins that reside in the nuclear envelope and endoplasmic reticulum (ER), respectively [10]
Dominant-negative strategies are of proven efficacy in studying the function of AAAϩ ATPases and GTPases in membrane dynamics, in particular when redundancy complicates the analysis of phenotypes [18, 19]
Summary
TorsinB is an AAAϩ ATPase of unknown function. Results: ATPase-arrested TorsinB induces the formation of LULL1-enriched, luminally constricted ER membranes requiring a highly conserved C-terminal motif in TorsinB. Of the four Torsins present in humans (TorsinA, TorsinB, Torsin2A, and Torsin3A), TorsinA (TorA) is the best studied due to its association with the disease Early Onset Torsion Dystonia, a disorder caused by the deletion of a glutamate residue (TorA⌬E) near the C terminus of the protein [2] This mutation leads to perinuclear inclusions in the cell [3,4,5,6,7], and strongly compromises TorA binding to lamina-associated polypeptide 1 (LAP1) and the related protein LULL1 [8, 9], which are type II transmembrane proteins that reside in the nuclear envelope and ER, respectively [10]. A similar phenotype is seen in LAP1-deficient mice, the nuclear blebbing phenotype is no longer restricted to neuronal tissues [13] Both LAP1 and LULL1 function to activate the dormant ATPase activity of TorsinA and TorsinB [9], only LAP1 localizes exclusively to the NE due to its association with the nuclear lamina [14]. The membrane-molding activity of TorsinB depends on LULL1, leading us to propose a novel role for this activating cofactor
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