SEL1L preserves CD8+ T-cell survival and homeostasis by fine-tuning PERK signaling and the IL-15 receptor-mediated mTORC1 axis
SEL1L-mediated endoplasmic reticulum-associated degradation (ERAD) plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins. However, it remains unclear how SEL1L regulates peripheral T-cell survival and homeostasis. Herein, we found that SEL1L def...
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Veröffentlicht in: | Cellular & molecular immunology 2023-10, Vol.20 (10), p.1232-1250 |
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Zusammenfassung: | SEL1L-mediated endoplasmic reticulum-associated degradation (ERAD) plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins. However, it remains unclear how SEL1L regulates peripheral T-cell survival and homeostasis. Herein, we found that SEL1L deficiency led to a greatly reduced frequency and number of mature T cells, which was further validated by adoptive transfer experiments or bone marrow chimera experiments, accompanied by the induction of multiple forms of cell death. Furthermore, SEL1L deficiency selectively disrupted naïve CD8
+
T-cell homeostasis, as indicated by the severe loss of the naïve T-cell subset but an increase in the memory T-cell subset. We also found that SEL1L deficiency fueled mTORC1/c-MYC activation and induced a metabolic shift, which was largely attributable to enhanced expression of the IL-15 receptor α and β chains. Mechanistically, single-cell transcriptomic profiling and biochemical analyses further revealed that
Sel1l
−/−
CD8
+
T cells harbored excessive ER stress, particularly aberrant activation of the PERK-ATF4-CHOP-Bim pathway, which was alleviated by supplementing IL-7 or IL-15. Importantly, PERK inhibition greatly resolved the survival defects of
Sel1l
−/−
CD8
+
T cells. In addition, IRE1α deficiency decreased mTORC1 signaling in
Sel1l
−/−
naïve CD8
+
T cells by downregulating the IL-15 receptor α chain. Altogether, these observations suggest that the ERAD adaptor molecule SEL1L acts as an important checkpoint for preserving the survival and homeostasis of peripheral T cells by regulating the PERK signaling cascade and IL-15 receptor-mediated mTORC1 axis. |
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ISSN: | 2042-0226 1672-7681 2042-0226 |
DOI: | 10.1038/s41423-023-01078-x |