@article{84dcf52636d34c5ab3ad572a52a78559,
title = "A UPF3-mediated regulatory switch that maintains RNA surveillance",
abstract = "Nonsense-mediated decay (NMD) is an RNA decay pathway that downregulates aberrant mRNAs and a subset of normal mRNAs. The regulation of NMD is poorly understood. Here we identify a regulatory mechanism acting on two related UPF (up-frameshift) factors crucial for NMD: UPF3A and UPF3B. This regulatory mechanism, which reduces the level of UPF3A in response to the presence of UPF3B, is relieved in individuals harboring UPF3B mutations, leading to strongly increased steady-state levels of UPF3A. UPF3A compensates for the loss of UPF3B by regulating several NMD target transcripts, but it can also impair NMD, as it competes with the stronger NMD activator UPF3B for binding to the essential NMD factor UPF2. This deleterious effect of UPF3A protein is prevented by its destabilization using a conserved UPF3B-dependent mechanism. Together, our results suggest that UPF3A levels are tightly regulated by a post-transcriptional switch to maintain appropriate levels of NMD substrates in cells containing different levels of UPF3B.",
author = "Chan, {Wai Kin} and Bhalla, {Angela D.} and {Le Hir}, Herv{\'e} and Nguyen, {Lam Son} and Lulu Huang and Jozef G{\'e}cz and Wilkinson, {Miles F.}",
note = "Funding Information: We thank J. Lykke-Andersen (University of Colorado) for several independent aliquots of antibodies against UPF1, UPF2, UPF3A and UPF3B, as well as the MS2-UPF1 and MS2-UPF2 constructs; L. Maquat (University of Rochester) for the T7-UPF2 constructs; M. Hentze (European Molecular Biology Labortaory, Heidelberg), A. Kulozik (University of Heidelberg,) and N. Gehring (University of Heidelberg) for human UPF3A and UPF3B constructs; M. Moore (University of Massachusetts) and A.-B. Shyu (University of Texas-Houston) for their polysome protocols; C. Shoubridge and L. Vandeleur (University of Adelaide) for culturing Epstein-Barr virus–immortalized B cell lines; and C. Schwartz and A. Srivastava (JC Self Research Institute of Human Genetics) for sharing the lymphoblastoid cell lines from family 1. Finally, we thank the many investigators whose publications inspired this work; we apologize that there is insufficient space to acknowledge them and reference all of their relevant publications. This work was funded by the US National Institutes of Health grant GM058595 (M.F.W.) and an Australian National Health and Medical Research Council grant (J.G.).",
year = "2009",
month = jul,
doi = "10.1038/nsmb.1612",
language = "English",
volume = "16",
pages = "747--753",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "Nature Research",
number = "7",
}