Format

Send to

Choose Destination
J Biol Chem. 2016 Apr 29;291(18):9469-81. doi: 10.1074/jbc.M115.709337. Epub 2016 Mar 7.

Site-specific Proteolysis Mobilizes TorsinA from the Membrane of the Endoplasmic Reticulum (ER) in Response to ER Stress and B Cell Stimulation.

Author information

1
From the Departments of Molecular Biophysics and Biochemistry and.
2
the Department of Translational Tumor Immunology, The Wistar Institute, Philadelphia, Pennsylvania 19104.
3
From the Departments of Molecular Biophysics and Biochemistry and Cell Biology, Yale University, New Haven, Connecticut 06520 and christian.schlieker@yale.edu.

Abstract

Torsin ATPases are the only representatives of the AAA+ ATPase family that reside in the lumen of the endoplasmic reticulum (ER) and nuclear envelope. Two of these, TorsinA and TorsinB, are anchored to the ER membrane by virtue of an N-terminal hydrophobic domain. Here we demonstrate that the imposition of ER stress leads to a proteolytic cleavage event that selectively removes the hydrophobic domain from the AAA+ domain of TorsinA, which retains catalytic activity. Both the pharmacological inhibition profile and the identified cleavage site between two juxtaposed cysteine residues are distinct from those of presently known proteases, suggesting that a hitherto uncharacterized, membrane-associated protease accounts for TorsinA processing. This processing occurs not only in stress-exposed cell lines but also in primary cells from distinct organisms including stimulated B cells, indicating that Torsin conversion in response to physiologically relevant stimuli is an evolutionarily conserved process. By establishing 5-nitroisatin as a cell-permeable inhibitor for Torsin processing, we provide the methodological framework for interfering with Torsin processing in a wide range of primary cells without the need for genetic manipulation.

KEYWORDS:

AAA+ ATPase; ER quality control; Torsin; endoplasmic reticulum stress (ER stress); intramembrane proteolysis; membrane protein; membrane trafficking

PMID:
26953341
PMCID:
PMC4850287
DOI:
10.1074/jbc.M115.709337
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center