Role of SMG-1-mediated Upf1 phosphorylation in mammalian nonsense-mediated mRNA decay.

SMG-1, a member of the PIKK (phosphoinositide 3-kinase-related kinase) family, plays a critical role in the mRNA quality control system known as nonsense-mediated mRNA decay (NMD). NMD protects cells from the accumulation of aberrant mRNAs with premature termination codons (PTCs) which encode nonfunctional or potentially harmful truncated proteins. SMG-1 directly phosphorylates Upf1 helicase, another key component of NMD, upon recognition of PTC on postspliced mRNA during the initial round of translation. Phosphorylated-Upf1 recruits the SMG-5/SMG-7 complex to induce ribosome dissociation and decapping-mediated decay. Phospho-Upf1 also recruits the SMG-6 endonuclease which might be involved in endo-cleavage. Upf1 ATPase/helicase activities are likely required for the activation of other mRNA decay enzymes and the mRNA-protein complex dissociation to complete NMD. At present, a variety of tools are available that can specifically suppress NMD, and it has become possible to examine the contribution of NMD in a variety of physiological and pathological conditions.