Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2

Posttranslational modifications represent a key step in modulating programmed death-1 (PD-1) functions, but the underlying mechanisms remain incompletely defined. Here, we report crosstalk between deglycosy-lation and ubiquitination in regulating PD-1 stability. We show that the removal of N-linked glycosylation is a prerequisite for efficient PD-1 ubiquitination and degradation. Murine double minute 2 (MDM2) is identified as an E3 ligase of deglycosylated PD-1. In addition, the presence of MDM2 facilitates glycosylated PD-1 inter-action with glycosidase NGLY1 and promotes subsequent NGLY1-catalyzed PD-1 deglycosylation. Func-tionally, we demonstrate that the absence of T cell-specific MDM2 accelerates tumor growth by primarily upregulating PD-1. By stimulating the p53-MDM2 axis, interferon-a (IFN-a) reduces PD-1 levels in T cells, which, in turn, exhibit a synergistic effect on tumor suppression by sensitizing anti-PD-1 immunotherapy. Our study reveals that MDM2 directs PD-1 degradation via a deglycosylation-ubiquitination coupled mech-anism and sheds light on a promising strategy to boost cancer immunotherapy by targeting the T cell-specific MDM2-PD-1 regulatory axis.

Automated summary

This study describes the crosstalk between deglycosylation and ubiquitination in regulating the stability of programmed death-1 (PD-1). MDM2 is identified as an E3 ligase involved in the deglycosylation and subsequent degradation of PD-1. Additionally, interferon-alpha (IFN-a) reduces PD-1 levels in T cells by stimulating the p53-MDM2 axis, which enhances the effectiveness of anti-PD-1 immunotherapy. These findings provide insights into a potential strategy for boosting cancer immunotherapy by targeting the T cell-specific MDM2-PD-1 regulatory axis.