The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A)-translation

Cells have evolved quality control mechanisms to ensure protein homeostasis by detecting and degrading aberrant mRNAs and proteins. A common source of aberrant mRNAs is premature polyadenylation, which can result in non-functional protein products. Translating ribosomes encountering poly(A) sequences are terminally stalled, followed by ribosome recycling and decay of the truncated nascent polypeptide via the ribosome-associated quality control (RQC). Here, we demonstrate that the conserved RNA-binding E3 ubiquitin ligase Makorin Ring Finger Protein 1 (MKRN1) promotes ribosome stalling at poly(A) sequences during RQC. We show that MKRN1 is positioned upstream of A-rich stretches and poly(A) tails in mRNAs through an interaction with the cytoplasmic poly(A)-binding protein (PABP). We uncover PABP, ribosomal protein RPS10, and additional translational regulators as main ubiquitylation substrates of MKRN1. Consequently, we propose that MKRN1 serves as a first line of poly(A) recognition at the mRNA level to prevent production of erroneous proteins, thus maintaining proteome integrity.