title: Rpl22 Loss Selectively Impairs αβ T Cell Development by Dysregulating Endoplasmic Reticulum Stress Signaling.
abstract: Although 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 αβ, but not γδ, T cell progenitors. Nevertheless, the basis by which Rpl22 loss selectively induces p53 in αβ T cell progenitors remained unclear. We show in this study that Rpl22 regulates the development of αβ T cells by restraining endoplasmic reticulum (ER) stress responses. In the absence of Rpl22, ER stress is exacerbated in αβ, but not γδ, T cell progenitors. The exacerbated ER stress in Rpl22-deficient αβ 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 αβ 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 αβ 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 αβ 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.
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19111.
authors.forename: Nehal R
authors.identifier: 0000-0002-6615-7401
authors.initials: NR
authors.lastname: Solanki
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and.
authors.forename: Jason E
authors.identifier: 0000-0003-1112-6736
authors.initials: JE
authors.lastname: Stadanlick
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and.
authors.forename: Ann-Cecile
authors.identifier: 0000-0001-6846-3165
authors.initials: AC
authors.lastname: Duc
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and.
authors.forename: Sang-Yun
authors.identifier: 0000-0001-6938-3781
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and.
authors.forename: Jens Peter Holst
authors.identifier: 0000-0002-8555-2626
authors.initials: JP
authors.lastname: Lauritsen
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and david.wiest@fccc.edu.
authors.forename: David L
authors.identifier: 0000-0002-0792-3188
authors.initials: DL
authors.lastname: Wiest
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage / Q000502:physiology; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D051379:Mice; D054504:Precursor Cells, T-Lymphoid / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000502:physiology*; D016693:Receptors, Antigen, T-Cell, alpha-beta; D012269:Ribosomal Proteins / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016601:RNA-Binding Proteins; C522051:RPL22 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53