The dystonia-associated Torsin1A sustains CLCC1 function in membrane fusion of the nuclear envelope for NPC biogenesis.

Abstract

DYT1 dystonia is an incurable movement disorder caused by a loss-of-function mutation in Torsin1A, an endoplasmic reticulum (ER)-resident AAA+ ATPase. Here, we use Drosophila and human cells to shed light on Torsins' mode of action. Fly germ cells lacking dTorsin arrest in development with defects in nuclear pore complex (NPC) biogenesis due to impaired nuclear envelope membrane fusion. We identify the conserved membrane protein Chloride Channel CLIC-like protein 1 (CLCC1) as a Torsin1A interaction partner whose absence phenocopies membrane fusion defects caused by Torsin deletion. CLCC1 is enriched at membrane fusion sites, and molecular dynamics (MD) simulations suggest that CLCC1 rings induce bilayer remodeling and lipid flux to initiate fusion of the outer and inner nuclear membranes. Remarkably, CLCC1 overexpression rescues defects associated with loss of Torsins, indicating that a main role of dTorsin/Torsin1A is to sustain CLCC1 functionality. Our findings inform a model of nuclear envelope membrane fusion and imply that modulating CLCC1 expression is a promising therapeutic prospect for DYT1 dystonia.