Rpl22 Loss Selectively Impairs αβ T Cell Development by Dysregulating Endoplasmic Reticulum Stress Signaling

Abstract

While 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, 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 here 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 PERK, 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.

Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy

“…Through applying a XBP-1-GFP reporter system, researchers revealed that the IRE-1α-XBP-1 branch is active in CD4 + CD8 + T cells from the thymus, indicating a role of the UPR in T cell development [37]. Another study reported that ablation of Rpl22 (RP ribosomal protein L22), which restrains ER stress, blocked the development of αβ, but not γδ T cell progenitors [38]. On the other hand, T cells containing a point mutation in the Kdelr1 gene (encoding ER chaperone KDEL receptor 1) have higher levels of phospho-eIF2α and impaired T cell survival [39].…”

Role of Autophagy in Cancer Cell Response to Nucleolar and Endoplasmic Reticulum Stress

“…It has been demonstrated that eL22 (Rpl22) loss exacerbates ER stress and strongly activates two of the three ER stress-signaling pathways, PERK and IRE1α [ 60 ]. Zhang et al have shown that UPR induction promotes the interaction between the r-proteins (uL18/rpL5, uL5/rpL11 and uL14/rpL23) and Hdm2 in PERK-dependent manner.…”

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“…RP defects or imbalances are associated with endoplasmic reticulum (ER) stress (Solanki et al., ), which is a known inducer of autophagy (Nie et al., ). In turn, ER stress triggers regulatory ubiquitination of 40S RPs (Higgins et al., ).…”