Shigella flexneri suppresses NF-κB activation by inhibiting linear ubiquitin chain ligation

Maarten F. De Jong, Zixu Liu, Didi Chen, Neal M. Alto

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The linear ubiquitin chain assembly complex (LUBAC) is a multimeric E3 ligase that catalyses M1 or linear ubiquitination of activated immune receptor signalling complexes (RSCs). Mutations that disrupt linear ubiquitin assembly lead to complex disease pathologies including immunodeficiency and autoinflammation in both humans and mice, but microbial toxins that target LUBAC function have not yet been discovered. Here, we report the identification of two homologous Shigella flexneri type III secretion system effector E3 ligases IpaH1.4 and IpaH2.5, which directly interact with LUBAC subunit Heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1L) and conjugate K48-linked ubiquitin chains to the catalytic RING-between-RING domain of HOIL-1-interacting protein (HOIP). Proteasomal degradation of HOIP leads to irreversible inactivation of linear ubiquitination and blunting of NF-κB nuclear translocation in response to tumour-necrosis factor (TNF), IL-1β and pathogen-associated molecular patterns. Loss of function studies in mammallian cells in combination with bacterial genetics explains how Shigella evades a broad spectrum of immune surveillance systems by cooperative inhibition of receptor ubiquitination and reveals the critical importance of LUBAC in host defence against pathogens.

Original languageEnglish (US)
Article number16084
JournalNature Microbiology
Volume1
Issue number7
DOIs
StatePublished - May 27 2016

Fingerprint

Shigella flexneri
Ubiquitin
Ligation
Ubiquitination
Ubiquitin-Protein Ligases
Shigella
Ligases
Heme
Interleukin-1
Immune System
Proteins
Tumor Necrosis Factor-alpha
Pathology
Mutation

ASJC Scopus subject areas

  • Microbiology
  • Applied Microbiology and Biotechnology
  • Immunology
  • Microbiology (medical)
  • Cell Biology
  • Genetics

Cite this

Shigella flexneri suppresses NF-κB activation by inhibiting linear ubiquitin chain ligation. / De Jong, Maarten F.; Liu, Zixu; Chen, Didi; Alto, Neal M.

In: Nature Microbiology, Vol. 1, No. 7, 16084, 27.05.2016.

Research output: Contribution to journalArticle

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