ER-phagy mediated by the UFM1 system. Upper panel: upon stalling of ER translocon-associated ribosomes, RPL26, a 60S ribosome subunit, and RPN1, a subunit of the OST complex, are UFMylated by the UFM1 E3 complex (the UFL1-UFBP1-CDK5RAP3 complex). CDK5RAP3 contains multiple sAIMs that bind to both UFM1 and autophagosome-localizing LC3 family proteins. The UFMylated RPL26 and RPN1 are recognized by CDK5RAP3 (probably in complex with UFL1 and UFBP1) through the sAIM. Subsequently, CDK5RAP3 binds to LC3 through other sAIMs to induce ER-phagy. Bottom panel: an ER-localizing reductase, NADH-cytochrome b5 reductase 3 (CYB5R3), is a substrate for UFM1. Although the induction cues are unknown, when UFBP1 is UFMylated in complex with UFL1, the E3 ligase activity toward CYB5R3 would increase. As a result, CYB5R3 undergoes UFMylation in a UFL1-UFBP1 complex-dependent manner. The UFMylated CYB5R3 interacts with the sAIM of CDK5RAP3, and the ER subdomains containing UFMylated CYB5R3 are transported to lysosomes through the interaction of other sAIM with LC3 family proteins.
