UPF2 is a core component of the nonsense-mediated mRNA decay (NMD) pathway, a translational surveillance mechanism that eliminates mRNAs containing premature stop codons 1. UPF2 functions as a molecular platform that bridges UPF1 to the exon junction complex (EJC) through interaction with UPF3B, forming the conserved UPF1-UPF2-UPF3 surveillance complex 2. Mechanistically, UPF2 stimulates both ATPase and RNA helicase activities of UPF1 cooperatively with UPF3B 2, while its MIF4G domains bind and unfold RNA secondary structures to stabilize single-stranded RNA, supporting UPF1's remodeling activity 3. UPF2 also directly interacts with the SURF complex and eRF3 at the ribosome, serving as a transient interaction hub for multiple NMD factors 1. Notably, UPF1's CH domain engagement with UPF2 precludes SMG6 endonuclease recruitment, suggesting distinct NMD complex configurations regulate pathway activity 4. Disease relevance: UPF3B mutations causing intellectual disability impair UPF2 binding affinity, with the Y160D mutation reducing binding ~40-fold 5. Clinically, disrupted UPF2 function correlates with altered NMD target stability and is implicated in inflammatory myofibroblastic tumors 6. UPF2 protein levels are regulated by both the ubiquitin-proteasome system and SMG1-dependent pathways 7.