Standing on the Shoulders of Giant Ribosomes: UPF1-dependent Surveillance of Translation Dynamics to Proteostasis

Up-frameshift 1 (UPF1) is best known as a key factor in nonsense-mediated mRNA decay (NMD), a well-conserved surveillance pathway that degrades mRNAs harboring premature termination codons (PTCs). The ATP-dependent RNA helicase UPF1 is recruited to ribosomes terminating at PTCs and triggers mRNA decay. Canonical NMD thereby limits the accumulation of truncated, potentially harmful polypeptides by rapidly eliminating faulty transcripts after the initial rounds of translation. However, emerging evidence from yeast to mammals indicates that UPF1 activity extends beyond simple degradation of PTC-containing mRNAs. Recent work links UPF1 to translating ribosomes, connecting translation dynamics with mRNA surveillance, co-translational quality control of nascent polypeptides, and aggresome targeting of aberrant translation products. These UPF1 functions beyond canonical NMD are increasingly recognized as important for cellular homeostasis. This review focuses on how UPF1 engages ribosomes to influence translation dynamics and coordinates the quality control of mRNA substrates and aberrant translation products. We further discuss the implications of these ribosome-coupled activities for diverse aspects of cellular physiology and disease.