Abstract
KDEL receptors are responsible for retrotransporting endoplasmic reticulum (ER) chaperones from the Golgi complex to the ER. Here we describe a role for KDEL receptor 1 (KDELR1) that involves the regulation of integrated stress responses (ISR) in T cells. Designing and using an N-ethyl-N-nitrosourea (ENU)-mutant mouse line, T-Red (naïve T-cell reduced), we show that a point mutation in KDELR1 is responsible for the reduction in the number of naïve T cells in this model owing to an increase in ISR. Mechanistic analysis shows that KDELR1 directly regulates protein phosphatase 1 (PP1), a key phosphatase for ISR in naïve T cells. T-Red KDELR1 does not associate with PP1, resulting in reduced phosphatase activity against eIF2α and subsequent expression of stress responsive genes including the proapoptotic factor Bim. These results demonstrate that KDELR1 regulates naïve T-cell homeostasis by controlling ISR.
Highlights
KDEL receptors are responsible for retrotransporting endoplasmic reticulum (ER) chaperones from the Golgi complex to the ER
Designing and using an N-ethyl-N-nitrosourea (ENU)-mutant mouse line, T-Red, we show that a point mutation in KDEL receptor 1 (KDELR1) is responsible for the reduction in the number of naıve T cells in this model owing to an increase in integrated stress responses (ISR)
Since phosphorylation of eIF2a increased in T-Red naıve T cells, we focused on the regulation of eIF2a phosphorylation to understand how the ISR pathway is activated by KDELR1 dysfunction in T-Red naıve T cells
Summary
KDEL receptors are responsible for retrotransporting endoplasmic reticulum (ER) chaperones from the Golgi complex to the ER. Integrated stress responses (ISR) are general stress-response programmes conserved from yeast and known to modulate cellular homeostasis by integrating various types of stress signals, including ER stress, amino-acid deprivation, infection with double-stranded RNA viruses, haem deficiency and oxidative stress[8,9,10] These diverse signals increase the activation status of four stress kinases—double-stranded RNA-dependent protein kinase R (PKR), RNA-dependent protein kinase-like ER kinase (PERK), eukaryotic initiation factor 2 (eIF2a) kinase general control non-repressed 2 (GCN2) and haem-regulated eIF2a kinase, each of which regulates phosphorylation at serine 51 of the a subunit of eIF2. We suggest that KDELR1 regulates ISR by controlling PP1 activity in naıve T cells in vivo
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