The reductase TMX1 contributes to ERAD by preferentially acting on membrane-associated folding-defective polypeptides

The Endoplasmic Reticulum (ER) is site of production of secretory and membrane proteins in eukaryotic cells. The ER does not contain catabolic devices and misfolded proteins generated in its lumen must be dislocated across the ER membrane before clearance by cytosolic proteasomes (ER-Associated Degr...

Full description

Saved in:
Bibliographic Details
Published in:Biochemical and biophysical research communications 2018-09, Vol.503 (2), p.938-943
Main Authors: Guerra, Concetta, Brambilla Pisoni, Giorgia, Soldà, Tatiana, Molinari, Maurizio
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
ENDOPLASMIC RETICULUM
Endoplasmic Reticulum - chemistry
Endoplasmic Reticulum - metabolism
Endoplasmic Reticulum-Associated Degradation
ER-Associated degradation
HEK293 Cells
Humans
MEMBRANE PROTEINS
Membrane Proteins - metabolism
Models, Molecular
Oxidation-Reduction
Oxido-reductase
OXIDOREDUCTASES
Peptides - chemistry
Peptides - metabolism
POLYPEPTIDES
Protein Domains
Protein Folding
Protein folding and quality control
Thioredoxins - metabolism
TMX1
Ubiquitin proteasome system
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The Endoplasmic Reticulum (ER) is site of production of secretory and membrane proteins in eukaryotic cells. The ER does not contain catabolic devices and misfolded proteins generated in its lumen must be dislocated across the ER membrane before clearance by cytosolic proteasomes (ER-Associated Degradation, ERAD). How misfolded proteins are dislocated across the ER membrane is a matter of controversy. For example, it remains to be established if polypeptide unfolding is always required. If unfolding is a pre-requisite for dislocation as emerging evidences seem to indicate, it is likely that the incorrect set of disulfide bonds established during unsuccessful folding-attempts that precede selection for ERAD must be reduced to eliminate tertiary and quaternary structures that could hamper dislocation. The lumen of the mammalian ER contains more than 20 members of the PDI family, a handful of which plays a role in ERAD. Here we add the atypical, membrane-bound reductase TMX1 to this list and we show that TMX1 preferentially acts on membrane-tethered folding-defective polypeptides essentially ignoring the same misfolded ectodomains, when not associated to the ER membrane. As such, TMX1 is the first example of a topology-specific client protein redox catalyst acting both in the folding and in the degradative pathways.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2018.06.099