Argonaute protein as a linker to command center of physiological processes

MicroRNAs （miRNAs） post-transcriptionally regulate gene expression by binding to target mRNAs with perfect or imperfect complementarity, recruiting an Argonaute （AGO） protein complex that usually results in degradation or translational repression of the target mRNA. AGO proteins function as the Slicer enzyme in miRNA and small interfering RNA （siRNA） pathways involved in human physiological and pathophysiological processes, such as antiviral responses and disease formation. Although the past decade has witnessed rapid advancement in studies of AGO protein functions, to further elucidate the molecular mechanism of AGO proteins in cellular function and biochemical process is really a challenging area for researchers. In order to understand the molecular causes underlying the pathological processes, we mainly focus on five fundamental problems of AGO proteins, including evolution, functional domain, subcellular location, post-translational modification and protein-protein interactions. Our discussion highlight their roles in early diagnosis, disease prevention, drug target identification, drug response, etc.

Argonaute(AGO)proteins play an essential role in mediating BMP9-induced osteogenic signaling in mesenchymal stem cells(MSCs)

As multipotent progenitor cells,mesenchymal stem cells(MSCs)can renew themselves and give rise to multiple lineages including osteoblastic,chondrogenic and adipogenic lineages.It’s previously shown that BMP9 is the most potent BMP and induces osteogenic and adipogenic differentiation of MSCs.However,the molecular mechanism through which BMP9 regulates MSC differentiation remains poorly understood.Emerging evidence indicates that noncoding RNAs,especially microRNAs,may play important roles in regulating MSC differentiation and bone formation.As highly conserved RNA binding proteins,Argonaute(AGO)proteins are essential components of the multi-protein RNA-induced silencing complexes(RISCs),which are critical for small RNA biogenesis.Here,we investigate possible roles of AGO proteins in BMP9-induced lineage-specific differentiation of MSCs.We first found that BMP9 upregulated the expression of Ago1,Ago2 and Ago3 in MSCs.By engineering multiplex siRNA vectors that express multiple siRNAs targeting individual Ago genes or all four Ago genes,we found that silencing individual Ago expression led to a decrease in BMP9-induced early osteogenic marker alkaline phosphatase(ALP)activity in MSCs.Furthermore,we demonstrated that simultaneously silencing all four Ago genes significantly diminished BMP9-induced osteogenic and adipogenic differentiation of MSCs and matrix mineralization,and ectopic bone formation.Collectively,our findings strongly indicate that AGO proteins and associated small RNA biogenesis pathway play an essential role in mediating BMP9-induced osteogenic differentiation of MSCs.

A novel strategy to inhibit the reproduction and translation of hepatitis C virus

Hepatitis C virus (HCV), a positive single-stranded RNA virus, is a major cause of liver disease in humans. Herein we report a novel strategy to inhibit the reproduction and translation of HCV using a short RNA, named an Additional RNA, to activate the endonuclease activity of Argonaute 2 (Ago2). In the presence of the Additional RNA, the HCV genome RNA has the requisite 12 nucleotides of base-pairing with microRNA-122. This activates the endonuclease activity of Ago2, resulting in cleavage and release of the HCV genome RNA from Ago2 and microRNA-122. The free HCV genome RNA would be susceptible to intracellular degradation, effectively inhibiting its reproduction and translation. This study presents a new method to inhibit HCV that may hold great potential for HCV treatment in the future.