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Sorting nexin 6 interacts with Cullin3 and regulates programmed death ligand 1 expression

Chinmoy Ghosh1, Yanli Xing2, Suhua Li1

  • 1Department of Oral and Craniofacial Molecular Biology, Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, VA, USA.

FEBS Letters
|September 12, 2021
PubMed

Insights

Sorting nexin 6 (SNX6) regulates programmed death ligand 1 (PD-L1) protein levels by controlling its degradation. SNX6 impacts PD-L1 stability, not its mRNA, revealing a new mechanism in cancer immune evasion.

Area of Science:

  • Molecular Biology
  • Cancer Immunology
  • Cell Biology

Background:

  • Programmed death ligand 1 (PD-L1) is crucial for cancer cells to evade immune responses.
  • The precise molecular mechanisms governing PD-L1 expression remain incompletely understood.

Purpose of the Study:

  • To identify novel regulators of PD-L1 expression.
  • To elucidate the molecular mechanisms by which SNX6 influences PD-L1 levels.

Main Methods:

  • Investigated the role of sorting nexin 6 (SNX6) in PD-L1 regulation using knockdown experiments.
  • Analyzed PD-L1 protein and mRNA levels.
  • Examined the interaction between SNX6, Cullin3, and speckle-type POZ protein using co-immunoprecipitation assays.

Main Results:

  • Knockdown of SNX6 significantly reduced PD-L1 protein levels but did not affect PD-L1 mRNA levels.
  • SNX6 was found to interact with Cullin3, an E3 ubiquitin ligase involved in PD-L1 degradation.
  • SNX6 binding to Cullin3 decreased the interaction between Cullin3 and speckle-type POZ protein, thereby reducing PD-L1 ubiquitination and degradation.

Conclusions:

  • Sorting nexin 6 (SNX6) is a novel regulator of PD-L1 protein stability.
  • SNX6 modulates PD-L1 levels by influencing its ubiquitination and degradation pathway via Cullin3.
  • This discovery provides a new molecular target for modulating PD-L1 expression in cancer therapy.
Keywords:
Cullin3PD-L1SNX6SPOPimmune checkpointimmunotherapy

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