Model depicting the role of CNX in regulating proteostasis of misfolded GPI-APs. CNX functions as a traffic officer in the busy intersection of the ER, juggling incoming nascent proteins for folding and refolding cycles (i) and directing correctly folded proteins for ER-export and secretion (ii) or terminally misfolded proteins for ER clearance pathways (iii and iv). During steady-state conditions, newly synthesized proteins (i) displace misfolded GPI-APs from CNX and free them to be cleared by the RESET pathway (iv), which is mediated by Tmp21 and p24 family proteins. Once released to the cell surface via RESET, misfolded GPI-APs may be internalized for lysosomal degradation or potentially be deposited in the extracellular matrix. Thus, blocking new protein synthesis allows CNX to engage with misfolded GPI-APs indefinitely and extends their half-life. Conversely, upregulation of PQC substrates either through induction of new protein synthesis or through the inhibition or saturation of ER-localized degradation pathways (shown as red “x”s) overwhelms CNX, forcing CNX to rapidly release the misfolded GPI-APs for RESET and eventual secretion to the cell surface.