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Rpl22 Loss Selectively Impairs alphabeta T Cell Development by Dysregulating Endoplasmic Reticulum Stress Signaling
J Immunol. 2016 Aug 3;197(6) :2280-9
PMID: 27489283 PMCID: PMC5011012 URL: http://www.ncbi.nlm.nih.gov/pubmed/27489283
AbstractAlthough ribosomal proteins (RP) are thought to primarily facilitate biogenesis of the ribosome and its ability to synthesize protein, emerging evidence suggests that individual RP can perform critical regulatory functions that control developmental processes. We showed previously that despite the ubiquitous expression of the RP ribosomal protein L22 (Rpl22), germline ablation of Rpl22 in mice causes a selective, p53-dependent block in the development of alphabeta, but not gammadelta, T cell progenitors. Nevertheless, the basis by which Rpl22 loss selectively induces p53 in alphabeta T cell progenitors remained unclear. We show in this study that Rpl22 regulates the development of alphabeta T cells by restraining endoplasmic reticulum (ER) stress responses. In the absence of Rpl22, ER stress is exacerbated in alphabeta, but not gammadelta, T cell progenitors. The exacerbated ER stress in Rpl22-deficient alphabeta T lineage progenitors is responsible for selective induction of p53 and their arrest, as pharmacological induction of stress is sufficient to induce p53 and replicate the selective block of alphabeta T cells, and attenuation of ER stress signaling by knockdown of protein kinase R-like ER kinase, an ER stress sensor, blunts p53 induction and rescues development of Rpl22-deficient alphabeta T cell progenitors. Rpl22 deficiency appears to exacerbate ER stress by interfering with the ability of ER stress signals to block new protein synthesis. Our finding that Rpl22 deficiency exacerbates ER stress responses and induces p53 in alphabeta T cell progenitors provides insight into how a ubiquitously expressed RP can perform regulatory functions that are selectively required by some cell lineages but not others.
NotesSolanki, Nehal R Stadanlick, Jason E Zhang, Yong Duc, Ann-Cecile Lee, Sang-Yun Lauritsen, Jens Peter Holst Zhang, Zhiqiang Wiest, David L R01 AI110985/AI/NIAID NIH HHS/United States J Immunol. 2016 Aug 3. pii: 1600815.