The deubiquitinase USP4 stabilizes the SCFFBXO24 ubiquitin E3 ligase to regulate immunity in experimental pneumonia

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Updated: Aug 7, 2026

In-vitro Reconstitution of Bacterial Ubiquitination and VCP/p97-mediated Elimination
07:58

In-vitro Reconstitution of Bacterial Ubiquitination and VCP/p97-mediated Elimination

Published on: January 2, 2026

Ilknur Yurtsever1, Daniela Farkas1, Alex Cornwell1

  • 1Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Davis Heart and Lung Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Nature Communications
|August 4, 2026
PubMed

Insights

The bacterium Haemophilus influenzae type B (HiB) protects the F-box only protein 24 (FBXO24) from degradation by reducing its ubiquitylation. This bacterial mechanism impairs innate immune defenses during pneumonia.

Area of Science:

  • Cellular Biology
  • Immunology
  • Microbiology

Background:

  • The SCFFBXO24 ubiquitin ligase regulates vital biological processes by targeting proteins for degradation.
  • Mechanisms controlling the cellular levels of FBXO24, a key receptor subunit, are not well understood.

Purpose of the Study:

  • To investigate how Haemophilus influenzae type B (HiB) affects FBXO24 stability.
  • To elucidate the role of deubiquitylation in HiB-mediated immune evasion.

Main Methods:

  • Utilized THP-1 macrophage cells and experimental HiB pneumonia models.
  • Investigated the deubiquitylation activity of ubiquitin-specific peptidase 4 (USP4).
  • Employed nanoparticle delivery of USP4 siRNA and genetic disruption of Fbxo24 in mice.

Main Results:

  • HiB infection reduces FBXO24 ubiquitylation and subsequent lysosomal degradation in macrophages.
  • USP4 mediates FBXO24 deubiquitylation and stabilization in a Toll-like receptor 4 (TLR4)-dependent manner.
  • USP4 inhibition or Fbxo24 disruption in mice reduced bacterial load and lung injury severity.

Conclusions:

  • Bacterial pathogens can manipulate host deubiquitylation pathways to stabilize E3 ligase components.
  • This bacterial strategy impairs innate host defense mechanisms, contributing to disease pathogenesis.

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