FIGURE 6:

Based on the presented data, a plausible scenario can be drawn in which a mislocalized protein (MLP) that has not translocated into the ER is bound to the ER membrane by virtue of hydrophobic segments of its transmembrane (TM) domain and/or hydrophobic segments within its signal sequence (SS). Bag6 interaction with hydrophobic segments within the MLP would then enable recruitment of the p97 adaptor Ubxd8 (via its UBA domain). Polyubiquitination of the MLP (by virtue of the ribosome quality control ligase LTN1, RNF126, or another E3 ligase) would enable recruitment of AIRAPL, an additional p97 adaptor to the polyubiquitinated MLP.