KDEL receptor 1 regulates T-cell homeostasis via PP1 that is a key phosphatase for ISR

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 (naive T-cell reduced), we show that a point mutation in KDELR1 is responsible for the reduction in the number of naive 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 naive T cells. T-Red KDELR1 does not associate with PP1, resulting in reduced phosphatase activity against eIF2 alpha and subsequent expression of stress responsive genes including the proapoptotic factor Bim. These results demonstrate that KDELR1 regulates naive T-cell homeostasis by controlling ISR.