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 deglycosylation 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 interaction with glycosidase NGLY1 and promotes subsequent NGLY1-catalyzed PD-1 deglycosylation. Functionally, 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-α (IFN-α) 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 mechanism and sheds light on a promising strategy to boost cancer immunotherapy by targeting the T cell-specific MDM2-PD-1 regulatory axis.
Pubmed ID: 37379210 RIS Download
Research resources used in this publication
Additional research tools detected in this publication
None foundAntibodies used in this publication
- Cleaved Caspase-3 (Asp175) Antibody (RRID:AB_2341188)
- Ki-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (RRID:AB_2620142)
- Rabbit monoclonal D4W2Z anti-CD8 (RRID:AB_2756376)
- FOXP3 Monoclonal Antibody (FJK-16s), PE, eBioscience (RRID:AB_465936)
- Granzyme B Monoclonal Antibody (NGZB), PE, eBioscience (RRID:AB_10870787)
- Granzyme B Monoclonal Antibody (NGZB), PerCP-eFluor™ 710, eBioscience (RRID:AB_11219476)
- TNF alpha Monoclonal Antibody (MP6-XT22), PerCP-eFluor™ 710, eBioscience (RRID:AB_1834445)
- IFN gamma Monoclonal Antibody (XMG1.2), PerCP-Cyanine5.5, eBioscience (RRID:AB_1107020)
- PE/Cyanine7 anti-mouse CD279 (PD-1) (RRID:AB_572017)
- PerCP/Cyanine5.5 anti-mouse CD45 (RRID:AB_893340)
- FITC anti-mouse/human CD44 (RRID:AB_312956)
- PerCP/Cyanine5.5 anti-mouse CD25 (RRID:AB_893288)
- PE anti-mouse CD8a (RRID:AB_312747)
- APC anti-mouse CD4 (RRID:AB_312697)
- TCF11/NRF1 (D5B10) Rabbit mAb (RRID:AB_11178947)
- Beta Actin antibody (RRID:AB_2687938)
- Mouse Anti-Ubiquitinylated proteins Monoclonal antibody, Unconjugated, Clone fk2 (RRID:AB_612093)
- NGLY1 Polyclonal Antibody (RRID:AB_2763292)
- Rabbit anti-NGLY1 Antibody, Affinity Purified (RRID:AB_2891467)
- Monoclonal Anti-Vinculin antibody produced in mouse (RRID:AB_477629)
- Anti-HA High Affinity; Rat monoclonal antibody (clone 3F10) (RRID:AB_390918)
- TP53-human (RRID:AB_628082)
- DDDDK-Tag (ECS/Enterokinase Cleavage Site) Polyclonal Antibody (RRID:AB_591224)
- LC3B (D11) XP Rabbit mAb (RRID:AB_2137707)
- MDM2 (E3G5I) Rabbit mAb (RRID:AB_2936381)
- MDM2 (SMP14) (RRID:AB_627920)
- MDM2 (D1V2Z) (RRID:AB_2784534)
- InVivoPlus anti-mouse CD8α (RRID:AB_10950145)
- anti-mouse CD4 (RRID:AB_1107636)
- InVivoPlus anti-mouse PD-1 (CD279) (RRID:AB_10949053)
- PD-1 (D7D5W) XP® Rabbit mAb (Mouse Specific) (RRID:AB_2800041)
- CD279 (PD-1) Monoclonal Antibody (J116), eBioscience (RRID:AB_468671)
- PD-1 (D4W2J) XP® (RRID:AB_2728833)
Associated grants
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This is a list of tools and resources that we have found mentioned in this publication.
Cleaved Caspase-3 (Asp175) Antibody (antibody)
RRID:AB_2341188
This polyclonal targets Cleaved Caspase-3 (Asp175)
View all literature mentionsKi-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (antibody)
RRID:AB_2620142
This monoclonal targets Ki-67
View all literature mentionsRabbit monoclonal D4W2Z anti-CD8 (antibody)
RRID:AB_2756376
This recombinant monoclonal targets CD8
View all literature mentionsFOXP3 Monoclonal Antibody (FJK-16s), PE, eBioscience (antibody)
RRID:AB_465936
This monoclonal targets FOXP3
View all literature mentionsGranzyme B Monoclonal Antibody (NGZB), PE, eBioscience (antibody)
RRID:AB_10870787
This monoclonal targets Granzyme B
View all literature mentionsGranzyme B Monoclonal Antibody (NGZB), PerCP-eFluor™ 710, eBioscience (antibody)
RRID:AB_11219476
This monoclonal targets Granzyme B
View all literature mentionsTNF alpha Monoclonal Antibody (MP6-XT22), PerCP-eFluor™ 710, eBioscience (antibody)
RRID:AB_1834445
This monoclonal targets TNF alpha
View all literature mentionsIFN gamma Monoclonal Antibody (XMG1.2), PerCP-Cyanine5.5, eBioscience (antibody)
RRID:AB_1107020
This monoclonal targets IFN gamma
View all literature mentionsPE/Cyanine7 anti-mouse CD279 (PD-1) (antibody)
RRID:AB_572017
This monoclonal targets CD279
View all literature mentionsPerCP/Cyanine5.5 anti-mouse CD45 (antibody)
RRID:AB_893340
This monoclonal targets CD45
View all literature mentionsFITC anti-mouse/human CD44 (antibody)
RRID:AB_312956
This monoclonal targets CD44
View all literature mentionsPerCP/Cyanine5.5 anti-mouse CD25 (antibody)
RRID:AB_893288
This monoclonal targets CD25
View all literature mentionsPE anti-mouse CD8a (antibody)
RRID:AB_312747
This monoclonal targets CD8a
View all literature mentionsAPC anti-mouse CD4 (antibody)
RRID:AB_312697
This monoclonal targets CD4
View all literature mentionsTCF11/NRF1 (D5B10) Rabbit mAb (antibody)
RRID:AB_11178947
This monoclonal targets TCF11/NRF1 (D5B10) Rabbit mAb
View all literature mentionsBeta Actin antibody (antibody)
RRID:AB_2687938
This monoclonal targets Beta Actin
View all literature mentionsMouse Anti-Ubiquitinylated proteins Monoclonal antibody, Unconjugated, Clone fk2 (antibody)
RRID:AB_612093
This monoclonal targets Ubiquitinylated proteins
View all literature mentionsNGLY1 Polyclonal Antibody (antibody)
RRID:AB_2763292
This polyclonal targets NGLY1
View all literature mentionsRabbit anti-NGLY1 Antibody, Affinity Purified (antibody)
RRID:AB_2891467
This polyclonal targets NGLY1
View all literature mentionsMonoclonal Anti-Vinculin antibody produced in mouse (antibody)
RRID:AB_477629
This monoclonal targets Vinculin antibody produced in mouse
View all literature mentionsAnti-HA High Affinity; Rat monoclonal antibody (clone 3F10) (antibody)
RRID:AB_390918
This monoclonal targets HA
View all literature mentionsDDDDK-Tag (ECS/Enterokinase Cleavage Site) Polyclonal Antibody (antibody)
RRID:AB_591224
This polyclonal targets DDDDK-Tag (ECS/Enterokinase Cleavage Site)
View all literature mentionsLC3B (D11) XP Rabbit mAb (antibody)
RRID:AB_2137707
This monoclonal targets LC3B (D11) XP Rabbit mAb
View all literature mentionsMDM2 (E3G5I) Rabbit mAb (antibody)
RRID:AB_2936381
This monoclonal targets MDM2
View all literature mentionsMDM2 (SMP14) (antibody)
RRID:AB_627920
This monoclonal targets detection of MDM2, MDM2 p60 cleavage product and p53-MDM2 complexes
View all literature mentionsInVivoPlus anti-mouse CD8α (antibody)
RRID:AB_10950145
This monoclonal targets CD8α
View all literature mentionsInVivoPlus anti-mouse PD-1 (CD279) (antibody)
RRID:AB_10949053
This monoclonal targets PD-1 (CD279)
View all literature mentionsPD-1 (D7D5W) XP® Rabbit mAb (Mouse Specific) (antibody)
RRID:AB_2800041
This monoclonal targets PD-1
View all literature mentionsCD279 (PD-1) Monoclonal Antibody (J116), eBioscience (antibody)
RRID:AB_468671
This monoclonal targets CD279 (PD-1)
View all literature mentionsPD-1 (D4W2J) XP® (antibody)
RRID:AB_2728833
This monoclonal targets PD-1
View all literature mentionsSTOCK Mdm2tm2.1Glo/J (organism)
RRID:IMSR_JAX:031614
Mus musculus with name STOCK Mdm2tm2.1Glo/J from IMSR.
View all literature mentions
