# The contribution of Torsin ATPases to cellular protein quality control

> **NIH NIH F31** · YALE UNIVERSITY · 2020 · $45,520

## Abstract

PROJECT SUMMARY/ABSTRACT
 Torsins are essential ATPases that localize within the endoplasmic reticulum (ER)/nuclear envelope (NE)
membrane system where they carry out poorly defined functions. Mutations in TorsinA, one of the four human
Torsins, cause the debilitating neurological movement disorder DYT1 dystonia, which has no cure. Torsins are
unusual ATPases because they alone are inactive. To hydrolyze ATP, Torsins must interact with one of two
known transmembrane cofactors that reside within the ER/NE system, lamina associated polypeptide 1 (LAP1)
and luminal domain like LAP1 (LULL1). As DYT1 dystonia associated TorsinA mutations disrupt its interactions
with LAP1/LULL1, this active complex is critical for normal neural development. Of the four human Torsins, three
are stimulated by LAP1 and/or LULL1 but Torsin2A has an unknown activation mechanism. The hallmark
phenotype of Torsin loss-of-function is deformations of the inner nuclear membrane (INM) referred to as blebs
that sequester unique protein quality control (PQC) foci enriched for K48-linked polyubiquitinated proteins. The
combined loss of TorsinA, TorsinB, and Torsin3A in HeLa cells results in a moderate number of blebs, however,
the additional loss of Torsin2A has the strongest effect on blebs and causes the most to form. This suggests that
an additional, unknown activator for Torsin2A exists. While recent studies demonstrate that blebs are disrupted,
immature nuclear pore complexes (NPCs), many questions remain about the PQC foci within blebs. The source,
identity, and recruitment mechanism of the K48-ubiqutinated protein substrates remain unknown; however, my
preliminary studies suggest a role for the nucleoporin NDC1 in targeting PQC substrates to the INM. This unusual
PQC defect that arises upon Torsin deficiency likely contributes to DYT1 dystonia etiology as all models of this
disease demonstrate this phenotype. The overarching hypothesis of this proposal is that Torsins
participate in a specific PQC pathway that affects the stability of proteins require for normal NPC
biogenesis. I will determine the contribution to Torsin’s PQC pathway of specific chaperones I have identified
to localize within blebs. I will accomplish this by using a truncated viral protein that localizes specifically to blebs
in a ubiquitin-dependent manner. I will investigate the connection between NPC biogenesis and PQC by
exploring the role for NDC1 in targeting Torsin PQC substrates to the INM. To discover yet-unidentified Torsin
activators and pathways redundant to the Torsin/activator system, I will perform a genome wide CRISPR screen
in cells devoid of LAP1 and LULL1. These data will be compared to our previously conducted screens in 4 Torsin
knockout and wildtype cells. Discovering redundant pathways is a largely unexplored strategy that I expect will
have clinical relevance as modulating these proteins instead of TorsinA may represent a therapeutic opportunity
for DYT1 dystonia. The aims described ...

## Key facts

- **NIH application ID:** 10140852
- **Project number:** 1F31NS120528-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Sarah Margaret Prophet
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-09-25 → 2021-09-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140852

## Citation

> US National Institutes of Health, RePORTER application 10140852, The contribution of Torsin ATPases to cellular protein quality control (1F31NS120528-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10140852. Licensed CC0.

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