Ribosomal protein S3, a new substrate of Akt, serves as a signal mediator between neuronal apoptosis and DNA repair.
RPS3, a conserved, eukaryotic ribosomal protein of the 40 S subunit, is required for ribosome biogenesis. Because ribosomal proteins are abundant and ubiquitous, they may have additional extraribosomal functions. Here, we show that human RPS3 is a physiological target of Akt kinase and a novel mediator of neuronal apoptosis. NGF stimulation resulted in phosphorylation of threonine 70 of RPS3 by Akt, and this phosphorylation was required for Akt binding to RPS3. RPS3 induced neuronal apoptosis, up-regulating proapoptotic proteins Dp5/Hrk and Bim by binding to E2F1 and acting synergistically with it. Akt-dependent phosphorylation of RPS3 inhibited its proapoptotic function and perturbed its interaction with E2F1. These events coincided with nuclear translocation and accumulation of RPS3, where it functions as an endonuclease. Nuclear accumulation of RPS3 results in an increase in DNA repair activity to some extent, thereby sustaining neuronal survival. Abolishment of Akt-mediated RPS3 phosphorylation through mutagenesis accelerated apoptotic cell death and severely compromised nuclear translocation of RPS3. Thus, our findings define an extraribosomal role of RPS3 as a molecular switch that accommodates apoptotic induction to DNA repair through Akt-mediated phosphorylation.
Lee
Sang Bae
SB
Department of Molecular Cell Biology, Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
Kwon
Il-Sun
IS
Park
Jihye
J
Lee
Kyung-Hoon
KH
Ahn
Younghee
Y
Lee
Cheolju
C
Kim
Joon
J
Choi
Soo Young
SY
Cho
Sung-Woo
SW
Ahn
Jee-Yin
JY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D047468:Immunoprecipitation; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*
D012269:Ribosomal Proteins; C044152:ribosomal protein S3; D020932:Nerve Growth Factor; D051057:Proto-Oncogene Proteins c-akt