The HDM2-p53 loop is crucial for monitoring p53 level and human pathologies. 
Therefore, identification of novel molecules involved in this regulatory loop is 
necessary for understanding the dynamic regulation of p53 and treatment of human 
diseases. Here, we characterized that the ribosomal protein L6 binds to and 
suppresses the E3 ubiquitin ligase activity of HDM2, and subsequently attenuates 
HDM2-mediated p53 polyubiquitination and degradation. The enhanced p53 activity 
further slows down cell cycle progression and leads to cell growth inhibition. 
Conversely, the level of p53 is dramatically decreased upon the depletion of 
RPL6, indicating that RPL6 is essential for p53 stabilization. We also found 
that RPL6 translocalizes from the nucleolus to nucleoplasm under ribosomal 
stress, which facilitates its binding with HDM2. The interaction of RPL6 and 
HDM2 drives HDM2-mediated RPL6 polyubiquitination and proteasomal degradation. 
Longer treatment of actinomycin D increases RPL6 ubiquitination and destabilizes 
RPL6, and thereby putatively attenuates p53 response until the level of L6 
subsides. Therefore, RPL6 and HDM2 form an autoregulatory feedback loop to 
monitor the level of p53 in response to ribosomal stress. Together, our study 
identifies the crucial function of RPL6 in regulating HDM2-p53 pathway, which 
highlights the importance of RPL6 in human genetic diseases and cancers.