Unconventional secretion of misfolded proteins promotes adaptation to proteasome dysfunction in mammalian cells.
To safeguard proteomic integrity, cells rely on the proteasome to degrade aberrant polypeptides, but it is unclear how cells remove defective proteins that have escaped degradation owing to proteasome insufficiency or dysfunction. Here we report a pathway termed misfolding-associated protein secretion, which uses the endoplasmic reticulum (ER)-associated deubiquitylase USP19 to preferentially export aberrant cytosolic proteins. Intriguingly, the catalytic domain of USP19 possesses an unprecedented chaperone activity, allowing recruitment of misfolded proteins to the ER surface for deubiquitylation. Deubiquitylated cargos are encapsulated into ER-associated late endosomes and secreted to the cell exterior. USP19-deficient cells cannot efficiently secrete unwanted proteins, and grow more slowly than wild-type cells following exposure to a proteasome inhibitor. Together, our findings delineate a protein quality control (PQC) pathway that, unlike degradation-based PQC mechanisms, promotes protein homeostasis by exporting misfolded proteins through an unconventional protein secretion process.
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Jin-Gu
JG
Lee
Laboratory of Retinal Cell &Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Shokichi
S
Takahama
Biomedical Engineering and Physical Science Shared Resource, NIBIB, National Institutes of Health, Bethesda, Maryland 20892, USA.
Guofeng
G
Zhang
Laboratory of Retinal Cell &Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Stanislav I
SI
Tomarev
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Yihong
Y
Ye
D003600:Cytosol / Q000378:metabolism*; D010450:Endopeptidases / Q000172:deficiency / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D021381:Protein Transport / Q000502:physiology*; D040901:Proteomics / Q000379:methods
D010450:Endopeptidases; C559917:USP19 protein, human; D046988:Proteasome Endopeptidase Complex