It has been reported that ribosomal protein S3 (rpS3) functions as a ribosomal protein, a DNA repair endonuclease, a proapoptotic protein, and an essential subunit of the native NF-kappa B complex. However, it is unknown how rpS3 induces apoptosis in response to extracellular stresses. We report here that rpS3 sensitizes genotoxic stress-induced apoptosis by activating JNK through a caspase dependent manner. This apoptotic effect was shown to result from the physical interaction between rpS3 and TRADD, as assessed by coimmunoprecipitation. Moreover, GFP-rpS3 colocalized with TRADD around the plasma membrane and in the cytoplasm during apoptosis. Thus, rpS3 appears to be recruited to the death-inducing signaling complex (DISC) to induce apoptosis by interacting TRADD in response to extracellular stresses. Based on the findings of this study, we concluded that rpS3 is recruited to the DISC and plays a critical role in both genotoxic stress and cytokine induced apoptosis. (C) 2012 Elsevier Inc. All rights reserved.