Since the identification of
smg-4 , questions of how the domains of the protein may function to mediate mRNA surveillance have remained. In spite of the beautiful results with the human orthologues, hUpf3p and hUpf3-X, showing these nucleocytoplasmic shuttling proteins bind with Y14 to mRNAs 20nt upstream of exon-exon boundaries [Kim,V. N. et al. (2001) Science 293: 1832-1836, and Lykke-Andersen, J. et al. (2001) Science 293: 1836-1839], and in an RNP in association with CBP80 help mediate a 'pioneer' round of translation [Ishigaki Y et al. (2001) Cell 106:607-617], the domains responsible for these activities are not yet fully elucidated. Although overall sequence identity between the worm and human proteins is only 20%, there is 64% sequence similarity over one 336 a.a. stretch, and many potential functional domains are highly conserved. Interestingly, part of the most conserved domain (Aronoff, R. et al. (2001) Gene 268:153-164), similar to an RNP-1 -like RNA binding motif and essential for rescue of
smg-4 mutant animals, is spliced out from one variant, hUpf3delta, of the two human genes. Complex regulation of the encoded protein products is probable. The proline rich carboxy-terminal domain of SMG-4 is particularly intriguing, with its alternatively spliced extension and some similarity to a regulatory domain of MAP-4, containing hallmarks of a substrate for phosphorylation. The recent report of a proline rich domain responsible for nuclear export that is regulated by phosphorylation [Catez et al. (2002) MCB 22: 1126-1139], caused me to reexamine the SMG-4 sequence. It is clear that sequence identity (although only 15.5% overall) is shared between the two proteins (see Figure), and conserved elements include potential MAP Kinase sites. Perhaps when
smg-4 is phosphorylated in this domain, it will be actively exported along with its associated RNP to the cytoplasm. Whether the virus coopts the mRNA surveillance machinery in its lifecycle is a new question raised by this apparent similarity. Figure: Alignment of HSV-1 US11 protein and SMG-4 protein. If the serine at position 129 of the US11 sequence is mutated to phenylalanine the protein is retained in nucleoli.