Ribosomal Proteins L5 and L11 Cooperatively Inactivate c-Myc via RNA-induced Silencing Complex

Oncogene MYC is highly expressed in many human cancers and functions as a global regulator of ribosome biogenesis. Previously, we reported that ribosomal protein (RP) L11 binds to c-Myc and inhibits its transcriptional activity in response to ribosomal stress. Here, we show that another ribosomal protein L5, cooperatively with RPL11, guides the RISC complex to c-Myc mRNA and mediates the degradation of the mRNA, consequently leading to inhibition of c-Myc activity. Knocking down of RPL5 induced c-Myc expression at both mRNA and protein levels, while overexpression of RPL5 suppressed c-Myc expression and activity. Immunoprecipitation revealed that RPL5 binds to 3UTR of c-Myc mRNA and two subunits of RISC complex, TRBP and Ago2, mediating the targeting of c-Myc mRNA by miRNAs. Interestingly, RPL5 and RPL11 co-resided on c-Myc mRNA and suppressed c-Myc expression cooperatively. These findings uncover a mechanism by which these two RPs can cooperatively suppress c-Myc expression, allowing a tightly controlled ribosome biogenesis in cells.