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Updated: Jun 4, 2026

Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates
14:32

Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates

Published on: February 27, 2016

SIRT2-mediated deacetylation activates USP22 catalytic function for PD-L1 protein stabilization and tumor immune

Na Li1, Qiong Gao2, Huijun Jia3

  • 1Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China.

The Journal of Clinical Investigation
|June 2, 2026
PubMed

Insights

SIRT2 stabilizes PD-L1 protein, enhancing tumor immune evasion. Inhibiting SIRT2 boosts antitumor immunity and synergizes with PD-1/PD-L1 blockade, offering a new strategy against cancer.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immune checkpoint blockade (ICB) therapy, including PD-1/PD-L1 inhibitors, shows promise in cancer treatment but has limited efficacy in many patients.
  • Identifying mechanisms of PD-L1 regulation and resistance is crucial for improving ICB effectiveness.

Purpose of the Study:

  • To identify novel regulators of PD-L1 and explore their therapeutic potential in overcoming ICB resistance.
  • To elucidate the molecular mechanism by which SIRT2 influences PD-L1 expression and stability.

Main Methods:

  • Western blotting and immunoprecipitation to assess protein levels and interactions.
  • Ubiquitination assays to determine protein degradation pathways.
  • In vivo and in vitro cancer models to evaluate therapeutic efficacy.
  • Analysis of human cancer patient data (bladder cancer, melanoma) for correlation studies.

Main Results:

  • SIRT2 was identified as a key positive regulator of PD-L1 protein stability, independent of transcriptional control.
  • SIRT2 stabilizes PD-L1 by maintaining the protein levels and deubiquitinase activity of USP22.
  • SIRT2 directly deacetylates USP22, enhancing its catalytic activity and preventing its degradation.
  • SIRT2 inhibition synergized with PD-1/PD-L1 blockade and USP22 inhibition to enhance antitumor immunity.
  • Correlations between protein levels of SIRT2, USP22, and PD-L1 were observed in human bladder cancer and melanoma.

Conclusions:

  • A novel SIRT2-USP22-PD-L1 axis was defined, contributing to tumor immune evasion.
  • SIRT2 acts as a critical regulator of PD-L1 stability through USP22 deubiquitination.
  • Targeting SIRT2 presents a promising therapeutic strategy to enhance the efficacy of ICB in cancer treatment.
Keywords:
Cancer immunotherapyImmunologyOncology

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