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Updated: May 31, 2026

Depletion and Reconstitution of Macrophages in Mice
08:50

Depletion and Reconstitution of Macrophages in Mice

Published on: August 1, 2012

Macrophage USP9X attenuates colitis by restricting oncostatin M production via K27-linked deubiquitination of STAT1

Tao Zhang1, Fanyi Meng1, Wenjing Zhao1

  • 1Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.

Cellular & Molecular Immunology
|May 28, 2026
PubMed

Insights

Ubiquitin-specific peptidase 9X (USP9X) regulates intestinal inflammation by controlling STAT1 ubiquitination. Loss of USP9X exacerbates IBD, while its restoration offers therapeutic potential for inflammatory bowel disease.

Area of Science:

  • Biochemistry
  • Immunology
  • Molecular Biology

Background:

  • Posttranslational modifications critically influence inflammatory bowel disease (IBD) pathogenesis.
  • The precise roles of deubiquitinases in intestinal macrophages are not well understood.
  • Ubiquitin-specific peptidase 9X (USP9X) is identified as a key regulator in intestinal inflammation.

Purpose of the Study:

  • To investigate the role of USP9X in intestinal macrophages and its impact on IBD.
  • To elucidate the molecular mechanism by which USP9X regulates intestinal inflammation.
  • To explore USP9X as a potential therapeutic target for IBD.

Main Methods:

  • Assessed USP9X expression in UC patients and correlated it with disease severity.
  • Utilized myeloid-specific USP9X deletion and overexpression models in DSS- and TNBS-induced colitis.
  • Investigated the interaction between USP9X and signal transducer and activator of transcription 1 (STAT1) using biochemical assays.
  • Analyzed STAT1 ubiquitination, nuclear translocation, and transcriptional activity.
  • Measured Oncostatin M (OSM) expression and employed OSM neutralization in vivo.
  • Evaluated therapeutic potential using AAV9-mediated USP9X delivery.

Main Results:

  • USP9X expression is decreased in ulcerative colitis (UC) patients and correlates with disease severity.
  • Myeloid-specific deletion of USP9X exacerbates colitis, while overexpression ameliorates it.
  • USP9X interacts with STAT1, removing K27-linked polyubiquitin chains from lysine 544.
  • Loss of USP9X enhances STAT1 nuclear translocation and OSM expression, worsening inflammation.
  • STAT1 K544 mutation attenuates USP9X knockdown effects.
  • Neutralizing OSM abrogates the exacerbated colitis in USP9X-deficient mice.
  • AAV9-mediated USP9X delivery reduced intestinal inflammation.

Conclusions:

  • USP9X acts as a critical negative regulator of intestinal inflammation.
  • A USP9X-STAT1-OSM axis links ubiquitin editing to transcriptional regulation in IBD pathogenesis.
  • USP9X modulates STAT1 activity via K27-linked ubiquitination at K544.
  • Targeting the USP9X-STAT1-OSM pathway represents a potential therapeutic strategy for IBD.
Keywords:
K27-linked ubiquitinationOncostatin MSignal transducer and activator of transcription 1Ubiquitin-specific peptidase 9Xinflammatory bowel disease

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