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Molecular and Cellular Biology, May 2006, p. 3390-3400, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3390-3400.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role for Upf2p Phosphorylation in Saccharomyces cerevisiae Nonsense-Mediated mRNA Decay

Weirong Wang,^1, Iván J. Cajigas,^4, Stuart W. Peltz,^1,2 Miles F. Wilkinson,³ and Carlos I. González^4*

Department of Molecular Genetics and Microbiology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey,¹ PTC Therapeutics, 100 Corporate Court, South Plainfield, New Jersey,² Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas,³ Department of Biology, University of Puerto Rico, San Juan, Puerto Rico⁴

Received 17 November 2005/ Returned for modification 12 December 2005/ Accepted 13 February 2006

Premature termination (nonsense) codons trigger rapid mRNA decay by the nonsense-mediated mRNA decay (NMD) pathway. Two conserved proteins essential for NMD, UPF1 and UPF2, are phosphorylated in higher eukaryotes. The phosphorylation and dephosphorylation of UPF1 appear to be crucial for NMD, as blockade of either event in Caenorhabditis elegans and mammals largely prevents NMD. The universality of this phosphorylation/dephosphorylation cycle pathway has been questioned, however, because the well-studied Saccharomyces cerevisiae NMD pathway has not been shown to be regulated by phosphorylation. Here, we used in vitro and in vivo biochemical techniques to show that both S. cerevisiae Upf1p and Upf2p are phosphoproteins. We provide evidence that the phosphorylation of the N-terminal region of Upf2p is crucial for its interaction with Hrp1p, an RNA-binding protein that we previously showed is essential for NMD. We identify specific amino acids in Upf2p's N-terminal domain, including phosphorylated serines, which dictate both its interaction with Hrp1p and its ability to elicit NMD. Our results indicate that phosphorylation of UPF1 and UPF2 is a conserved event in eukaryotes and for the first time provide evidence that Upf2p phosphorylation is crucial for NMD.

W.W. and I.J.C. contributed equally to this work.

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