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• W1982757612 abstract "Membrane proteins that fail to be delivered to the endoplasmic reticulum must be rapidly degraded to avoid inappropriate aggregation and disruption of protein homeostasis. The mechanism of this process of mislocalized protein (MLP) degradation is unknown. Here Bag6, a chaperone complex involved in protein targeting, is identified as part of this mechanism. Bag6 interacts with and captures MLPs, coupling them to the ubiquitin-mediated degradation pathway. This could potentially achieve rapid degradation of MLPs without futile engagement of the cytosolic folding machinery. A substantial proportion of the genome encodes membrane proteins that are delivered to the endoplasmic reticulum by dedicated targeting pathways1. Membrane proteins that fail targeting must be rapidly degraded to avoid aggregation and disruption of cytosolic protein homeostasis2,3. The mechanisms of mislocalized protein (MLP) degradation are unknown. Here we reconstitute MLP degradation in vitro to identify factors involved in this pathway. We find that nascent membrane proteins tethered to ribosomes are not substrates for ubiquitination unless they are released into the cytosol. Their inappropriate release results in capture by the Bag6 complex, a recently identified ribosome-associating chaperone4. Bag6-complex-mediated capture depends on the presence of unprocessed or non-inserted hydrophobic domains that distinguish MLPs from potential cytosolic proteins. A subset of these Bag6 complex ‘clients’ are transferred to TRC40 for insertion into the membrane, whereas the remainder are rapidly ubiquitinated. Depletion of the Bag6 complex selectively impairs the efficient ubiquitination of MLPs. Thus, by its presence on ribosomes that are synthesizing nascent membrane proteins, the Bag6 complex links targeting and ubiquitination pathways. We propose that such coupling allows the fast tracking of MLPs for degradation without futile engagement of the cytosolic folding machinery." @default.
• W1982757612 created "2016-06-24" @default.
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• W1982757612 date "2011-07-01" @default.
• W1982757612 modified "2023-10-12" @default.
• W1982757612 title "Protein targeting and degradation are coupled for elimination of mislocalized proteins" @default.
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• W1982757612 doi "https://doi.org/10.1038/nature10181" @default.
• W1982757612 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3150218" @default.
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