SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay.

Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that detects and degrades mRNAs containing premature translation termination codons (PTCs). SMG-1 and Upf1 transiently form a surveillance complex termed "SURF" that includes eRF1 and eRF3 on post-spliced mRNAs during recognition of PTC. If an exon junction complex (EJC) exists downstream from the SURF complex, SMG-1 phosphorylates Upf1, the step that is a rate-limiting for NMD. We provide evidence of an association between the SURF complex and the ribosome in association with mRNPs, and we suggest that the SURF complex functions as a translation termination complex during NMD. We identified SMG-8 and SMG-9 as novel subunits of the SMG-1 complex. SMG-8 and SMG-9 suppress SMG-1 kinase activity in the isolated SMG-1 complex and are involved in NMD in both mammals and nematodes. SMG-8 recruits SMG-1 to the mRNA surveillance complex, and inactivation of SMG-8 induces accumulation of a ribosome:Upf1:eRF1:eRF3:EJC complex on mRNP, which physically bridges the ribosome and EJC through eRF1, eRF3, and Upf1. These results not only reveal the regulatory mechanism of SMG-1 kinase but also reveal the sequential remodeling of the ribosome:SURF complex to the predicted DECID (DECay InDucing) complex, a ribosome:SURF:EJC complex, as a mechanism of in vivo PTC discrimination.

N- and C-terminal Upf1 phosphorylations create binding platforms for SMG-6 and SMG-5:SMG-7 during NMD.

Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that detects and degrades mRNAs containing premature termination codons (PTCs). SMG-1-mediated Upf1 phosphorylation takes place in the decay inducing complex (DECID), which contains a ribosome, release factors, Upf1, SMG-1, an exon junction complex (EJC) and a PTC-mRNA. However, the significance and the consequence of Upf1 phosphorylation remain to be clarified. Here, we demonstrate that SMG-6 binds to a newly identified phosphorylation site in Upf1 at N-terminal threonine 28, whereas the SMG-5:SMG-7 complex binds to phosphorylated serine 1096 of Upf1. In addition, the binding of the SMG-5:SMG-7 complex to Upf1 resulted in the dissociation of the ribosome and release factors from the DECID complex. Importantly, the simultaneous binding of both the SMG-5:SMG-7 complex and SMG-6 to phospho-Upf1 are required for both NMD and Upf1 dissociation from mRNA. Thus, the SMG-1-mediated phosphorylation of Upf1 creates a binding platforms for the SMG-5:SMG-7 complex and for SMG-6, and triggers sequential remodeling of the mRNA surveillance complex for NMD induction and recycling of the ribosome, release factors and NMD factors.

Health management of adults with Turner syndrome: an attempt at multidisciplinary medical care by gynecologists in cooperation with specialists from other fields.

AIM: Since women with Turner Syndrome (TS) have various complications, they require comprehensive medical evaluation and multidisciplinary treatment. Although TS patients receive adequate care in childhood, many adults with TS do not. Since most TS adults attend gynecologists for hormone replacement therapy, we suggest gynecologists take primary responsibility for their management. In an attempt to provide TS patients with a comprehensive treatment regimen, we started multidisciplinary medical management in the Reproductive Health Clinic at Yokohama City University Hospital. To evaluate the efficacy of this medical care system, a retrospective analysis was conducted. METHODS: The clinical profiles of 57 TS patients were examined. The past histories, complications and clinical data of these patients were extracted from their medical records and examined clinically. Bone mineral density measurements of lumbar vertebrae (L(2-4)), anti-thyroid antibody titer measurements, hearing tests and cardiovascular MRI were also performed. RESULTS: Mean follow-up duration was 5.1 years (range, 1-8 years). At the time of transition, patients with complications developed in childhood, such as amenorrhea, osteopenia/osteoporosis, otitis media, thyroid dysfunction and cardiovascular disease were identified. All these complaints were successfully followed up in our adult care system. Several complications common to TS adults, such as glucose intolerance, liver dysfunction, hyperlypidemia and hypertension could be identified by our screening system. Patients were referred to specialists when necessary. CONCLUSION: Multidisciplinary health management in our Reproductive Health Clinic improved the status of medical care for TS adults.