Faithful translation of genetic information depends on the ability of the translational machinery to decode stop codons as termination signals. Although termination of protein synthesis is highly efficient, errors in decoding of stop codons may lead to the synthesis of C-terminally extended proteins. It was found that in eukaryotes such elongated proteins do not accumulate in cells. However, the mechanism for sequestration of C-terminally extended proteins is still unknown. Here we show that 3'-UTR-encoded polypeptides promote aggregation of the C-terminally extended proteins, and targeting to lysosomes. We demonstrate that 3'-UTR-encoded polypeptides can promote different levels of protein aggregation, similar to random sequences. We also show that aggregation of endogenous proteins can be induced by aminoglycoside antibiotics that promote stop codon read-through, by UAG suppressor tRNA, or by knokcdown of release factor 1. Furthermore, we find correlation between the fidelity of termination signals, and the predicted propensity of downstream 3'-UTR-encoded polypeptides to form intrinsically disordered regions. Our data highlight a new quality control mechanism for elimination of C-terminally elongated proteins.
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