A research team led by Professor Dr Niels Gehring from the Institute for Genetics showed that the coordinated interaction of three proteins plays a central role in nonsense-mediated mRNA decay (NMD). NMD is a mechanism in cells that destroys faulty RNA. Together, the proteins SMG1, SMG8, and SMG9 ensure that this mechanism is activated and functions reliably. Mutations in the genes SMG8 and SMG9 are associated with genetic diseases. However, for a long time it remained unclear within the complex what role the proteins they encode play in human cells. Gehring and his team have now demonstrated this in more detail. The study „SMG1:SMG8:SMG9-complex integrity supports efficient execution of nonsense-mediated mRNA decay" was published in the journal Nucleic Acids Research.
Nonsense-mediated mRNA decay (NMD) is one of the cell's most important regulatory systems. It ensures that defective messenger RNAs – i.e., copies of genetic blueprints – are detected and degraded before they can give rise to non-functional or potentially harmful proteins. The enzyme SMG1 plays a central role in this process: it activates NMD and thus triggers the degradation of defective mRNAs. In human cells, however, SMG1 does not act alone. Together with the proteins SMG8 and SMG9, it forms a stable protein complex.
To explore the function of SMG8 and SMG9 in a cellular context, the researchers specifically generated cell lines in which both proteins had been deactivated. "This way, we were able to analyse the actual role played by SMG8 and SMG9 in living cells," explains Gehring. "In a test tube, individual effects can be examined in isolation, but it is only within the cell that we can see just how stable or sensitive a complex control system really is."
Surprisingly, the NMD mechanism continued to function even without SMG8 or SMG9, although somewhat less efficiently. Defective mRNAs were therefore still being detected and degraded. "Our results show that SMG8 and SMG9 are not essential drivers of NMD," says Dr Volker Böhm, one of the authors of the study. "Rather, they help the mechanism to function more stably and reliably."
However, their true significance became apparent when the researchers subjected the system to additional stress. When SMG1 activity was reduced using a specific inhibitor, cells lacking SMG8 or SMG9 reacted much more sensitively than normal cells. Even minor disruptions were enough to severely impair the NMD mechanism. "As long as the complex is intact, the NMD process remains stable even under altered conditions. However, if either SMG8 or SMG9 is missing, the system becomes significantly more vulnerable," says Dr Sabrina Kueckelmann, first author of the study. This is similar to a moving car. An SMG1 car performs well even without SMG8 and SMG9. However, in difficult conditions, SMG8 and SMG9 act as driver assistance systems, much like ABS or traction control, ensuring a safe and reliable drive even in wet or icy conditions.
The study provides new insights into the organization of the SMG1:SMG8:SMG9 complex and demonstrates how additional proteins contribute to the stability of a key regulatory system within the cell. It was conducted within the framework of Collaborative Research Centre (CRC) 1678, "Systems-level consequences of fidelity changes in mRNA and protein biosynthesis", funded by the German Research Foundation (DFG).
