Pathogenic ubiquitination of GSDMB inhibits NK cell bactericidal functions

Justin M. Hansen, Maarten F. de Jong, Qi Wu, Li Shu Zhang, David B. Heisler, Laura T. Alto, Neal M. Alto

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Gasdermin B (GSDMB) belongs to a large family of pore-forming cytolysins that execute inflammatory cell death programs. While genetic studies have linked GSDMB polymorphisms to human disease, its function in the immunological response to pathogens remains poorly understood. Here, we report a dynamic host-pathogen conflict between GSDMB and the IpaH7.8 effector protein secreted by enteroinvasive Shigella flexneri. We show that IpaH7.8 ubiquitinates and targets GSDMB for 26S proteasome destruction. This virulence strategy protects Shigella from the bacteriocidic activity of natural killer cells by suppressing granzyme-A-mediated activation of GSDMB. In contrast to the canonical function of most gasdermin family members, GSDMB does not inhibit Shigella by lysing host cells. Rather, it exhibits direct microbiocidal activity through recognition of phospholipids found on Gram-negative bacterial membranes. These findings place GSDMB as a central executioner of intracellular bacterial killing and reveal a mechanism employed by pathogens to counteract this host defense system.

Original languageEnglish (US)
Pages (from-to)3178-3191.e18
JournalCell
Volume184
Issue number12
DOIs
StatePublished - Jun 10 2021
Externally publishedYes

Keywords

  • E3 ubiquitin ligase
  • GSDMB
  • GZMA
  • IpaH
  • gasdermin
  • inflammasome
  • lytic cell death
  • mucosal immunity
  • natural killer cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'Pathogenic ubiquitination of GSDMB inhibits NK cell bactericidal functions'. Together they form a unique fingerprint.

Cite this