Abstract
SummaryApproximately 30% of eukaryotic proteins contain hydrophobic signals for localization to the secretory pathway. These proteins can be mislocalized in the cytosol due to mutations in their targeting signals, certain stresses, or intrinsic inefficiencies in their translocation. Mislocalized proteins (MLPs) are protected from aggregation by the Bag6 complex and degraded by a poorly characterized proteasome-dependent pathway. Here, we identify the ubiquitin ligase RNF126 as a key component of the MLP degradation pathway. In vitro reconstitution and fractionation studies reveal that RNF126 is the primary Bag6-dependent ligase. RNF126 is recruited to the N-terminal Ubl domain of Bag6 and preferentially ubiquitinates juxtahydrophobic lysine residues on Bag6-associated clients. Interfering with RNF126 recruitment in vitro prevents ubiquitination, and RNF126 depletion in cells partially stabilizes a Bag6 client. Bag6-dependent ubiquitination can be recapitulated with purified components, paving the way for mechanistic analyses of downstream steps in this cytosolic quality control pathway.
Highlights
Protein quality control is essential for cellular homeostasis (Kim et al, 2013)
In vitro reconstitution and fractionation studies reveal that RNF126 is the primary Bag6-dependent ligase
RNF126 is recruited to the N-terminal Ubl domain of Bag6 and preferentially ubiquitinates juxtahydrophobic lysine residues on Bag6-associated clients
Summary
Failure to promptly recognize and degrade defective or superfluous proteins leads to their accumulation This accumulation of aberrant proteins can have several consequences, including protein aggregation, inappropriate interactions, damage to cellular membranes, induction of stress responses, and many others. The range of proteins it handles, and the myriad ways in which they can be defective, requires a highly flexible quality control system. This challenging task is not handled by a single pathway, but by multiple parallel pathways dedicated to different types of aberrant proteins (Buchberger et al, 2010; Fang and Mayor, 2012; Rodrigo-Brenni and Hegde, 2012). A current goal in the quality control field is to define the full complement of pathways, the components that comprise each pathway, and their respective client specificities
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