The nuclear envelope localization of DYT1 dystonia torsinA-?E requires the SUN1 LINC complex component.

ABSTRACT: BACKGROUND: DYT1 dystonia is an autosomal dominant neurological condition caused by a mutation that removes a single glutamic acid residue (?E) from the torsinA (torA) AAA+ protein. TorA appears to possess a nuclear envelope (NE) localized activity that requires Lamina-Associated-Polypeptide 1 (LAP1), which is an inner nuclear membrane localized torA-binding partner. Although hypoactive, the DYT1 dystonia torA-?E isoform often concentrates in the NE, suggesting that torA-?E also interacts with an NE-localized binding partner. RESULTS: We confirm that NE-localized torA-?E does not co-immunoprecipitate with LAP1, and find that torA-?E continues to concentrate in the NE of cells that lack LAP1. Instead, we find that variability in torA-?E localization correlates with the presence of the SUN-domain and Nesprin proteins that assemble into the LINC complex. We also find that siRNA depletion of SUN1, but not other LINC complex components, removes torA-?E from the NE. In contrast, the LAP1-dependent NE-accumulation of an ATP-locked torA mutant is unaffected by loss of LINC complex proteins. This SUN1 dependent torA-?E localization requires the torA membrane association domain, as well as a putative substrate-interaction residue, Y147, neither of which are required for torA interaction with LAP1. We also find that mutation of these motifs, or depletion of SUN1, decreases the amount of torA-WT that colocalizes with NE markers, indicating that each also underlies a normal NE-localized torA binding interaction. CONCLUSIONS: These data suggest that the disease causing ?E mutation promotes an association between torA and SUN1 that is distinct to the interaction between LAP1 and ATP-bound torA. This evidence for two NE-localized binding partners suggests that torA may act on multiple substrates and/or possesses regulatory co-factor partners. In addition, finding that the DYT1 mutation causes abnormal association with SUN1 implicates LINC complex dysfunction in DYT1 dystonia pathogenesis, and suggests a gain-of-function activity contributes to this dominantly inherited disease.

SUBMITTER: Jungwirth MT 

PROVIDER: S-EPMC3164226 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature