The Importance Of Nucleocytoplasmic Shuttling In SAMHD1-Mediated LINE-1 Suppression

As a host cell natural antiviral factor, with diverse biological functions and complex mechanisms, SAMHD1 has always been a hot subject in the field of molecular biology research. The further researches in recent years not only have revealed SAMHD1’s association with AGS and its potency in suppressing HIV infection, but also have demonstrated the ability of SAMHD1 in LINE-1 inhibition. LINE-1 exists in all kinds of mammalian cells, and its quantity is very large in human genome. Although LINE-1 transposition activity is usually very low, so it can not threaten the genome stability. But LINE-1 has been related to many genetic mutations and diseases. Once SAMHD1 loss its inhibition on LINE-1, it may cause severe consequences. However, the mechanism of SAMHD1 inhibiting LINE-1 is still not fully understood for now. According to the experiment results, we believe that in order to inhibit LINE-1, SAMHD1 reduces the expression of ORF2, as well as the ORF2-mediated reverse transcription of LINE-1 RNA. During the study, we found that multiple SAMHD1 mutations have significant difference in LINE-1 suppression. So we conducted the nucleocytoplasmic separation experiment. The experiment shows that cytoplasmic localization enhanced SAMHD1’s potency in inhibiting LINE-1 activity. So we infer that even though SAMHD1 contains a nuclear localization signal, and normally locates in the nucleus, it may achieve its inhibiting of LINE-1 in cytoplasm through a nucleocytoplasmic shuttling mechanism. Nucleocytoplasmic shuttling is very important for SAMHD1 inhibiting LINE-1, because the inhibition of LINE-1 needs SAMHD1 to be in cytoplasm first. The phenomenon of nucleocytoplasmic shuttling certainly provides new insights on the study of SAMHD1’s biological function as well as associated mechanisms. It also provides a theoretical basis for prevention and treatment research of SAMHD1 related diseases.