BAG6 and SGTA function in the quality control of mislocalised proteins (MLPs) by promoting and inhibiting the degradation of such proteins, respectively. Here (p. ), Stephen High and colleagues describe, for the first time, an interaction between the C-terminal domain of Rpn13, a proteasome-associated ubiquitin receptor that facilitates delivery of substrates for degradation, and the tetratricopeptide (TPR) domain of SGTA, and investigate the role of that interaction in the quality control of MLPs. Overexpressed SGTA associated with the proteasome and caused an increase in the levels of OP91, an N-terminal fragment of opsin that acts as an MLP. By contrast, overexpression of both SGTA and the C-terminal domain of Rpn13 decreased the proteasomal association of SGTA, and reduced steady-state levels of OP91 and another model MLP, indicating that when SGTA is titrated away from endogenous Rpn13, it can no longer delay the proteasomal degradation of MLPs. The phenomenon was MLP-specific, as Rpn13 and SGTA expression had no effect on the N-end rule degradation substrate ubiquitin–arginine–GFP. In addition, a point mutation in the TPR domain of SGTA perturbed both its proteasomal recruitment and its ability to increase OP91 levels when overexpressed. In conclusion, this study demonstrates that the BAG6–SGTA-dependent quality control of MLPs occurs, at least in part, at the proteasome as the recruitment of SGTA through Rpn13 is necessary for SGTA to modulate MLP levels.
