ER-RQC mediated by the UFM1 system. Step 1: the RQC collision sensor recognizes collided ribosomes and ubiquitinates the stagnant ribosomes as a marker of abnormal translation. The ubiquitinated ribosomes are recognized by the ribosome quality control trigger (RQT) complex, inducing forced subunit dissociation into the 40S and 60S subunits. Step 2: the UFM1 E3 complex ufmylates RPL26 on the 60S ribosomal subunit. Step 3: the UFM1 E3 complex stably binds to the 60S ribosomal subunit with UFMylated RPL26 through the UFIM of UFBP1. Thereafter, LTN1 and/or NEMF bind to the 60S subunit. LTN1 ubiquitinates the aberrant polypeptide, and NEMF forms a CAT-tail at its C terminus. Step 4: ANKZF1 releases the aberrant polypeptide. The LTN1-mediated polyubiquitinated polypeptide is subjected to proteasomal degradation. In an alternative pathway, Ala-tailed polypeptide is recognized and degraded by the two E3 ligases CRL2KLHDC10 and PIRH2/RCHY1, which is called an RQC-C pathway. The non-Ala-tailed abnormal products may induce aggregation, leading to apoptosis, and neurodegeneration.
