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.
D. Maslennikova, Harry J. M. Baird, Xinyue Ding et al.· Molecules and Cells· 2 citations· ⚡1
Patterning is fundamental to the development and maintenance of organisms, ensuring functional and structural organization. While patterning is well studied at the level of multicellular organisms, single cells also form spatial patterns. Stentor coeruleus is a ciliate that has been a classical system for studying patterning and morphogenesis due to its distinctive shape and organization of easily visible cortical structures. The cortex of Stentor contains two cytoskeletal layers: microtubules and a network of centrin-family EF-hand proteins, which form a branched network in the anterior half of the cell and long, thick bundles known as myonemes in the posterior half. Sfi1 family proteins scaffold the assembly of centrin filaments throughout the eukaryotes and support contractile myonemal systems in some ciliates. In Stentor, a set of Sfi1 proteins upregulated during regeneration maintains anterior/posterior differences in centrin patterning, and this loss disrupts both regeneration and contraction. RNAi-mediated knockdown revealed that temporally expressed Sfi1 genes correlate with distinct stages of oral primordium growth. Additionally, the knockdown of Sfi1 isoforms that results in reduced myoneme cables impairs contraction, such that cells fail to contract in response to a stimulus or do not fully contract. These findings suggest a model in which regionalized differences in the patterning of cytoskeletal assemblies can be modulated by the regionalized localization of scaffolding proteins.
Connie Yan, N. Steube, G. Dey et al.· Current Biology· 0 citations
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