An alternative UPF1 isoform drives conditional remodeling of nonsense-mediated mRNA decay

The nonsense-mediated mRNA decay (NMD) pathway monitors translation termination in order to degrade transcripts with premature stop codons and regulate thousands of human genes. Here, we show that an alternative mammalian-specific isoform of the core NMD factor UPF1, termed UPF1_LL , enables condition-dependent remodeling of NMD specificity. Previous studies indicate that the extension of a conserved regulatory loop in the UPF1_LL helicase core confers a decreased propensity to dissociate from RNA upon ATP hydrolysis relative to UPF1_SL , the major UPF1 isoform. Using biochemical and transcriptome-wide approaches, we find that UPF1_LL can circumvent the protective RNA binding proteins PTBP1 and hnRNP L to preferentially bind and down-regulate transcripts with long 3'UTRs normally shielded from NMD. Unexpectedly, UPF1_LL supports induction of NMD on new populations of substrate mRNAs in response to activation of the integrated stress response and impaired translation efficiency. Thus, while canonical NMD is abolished by moderate translational repression, UPF1_LL activity is enhanced, offering the possibility to rapidly rewire NMD specificity in response to cellular stress.