Related Experiment Video

Updated: Nov 8, 2025

Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice
08:09

Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice

Published on: March 24, 2017

8.3K

X-linked inhibitor of apoptosis protein (XIAP) inhibition in systemic sclerosis (SSc)

Christina Bergmann1, Ludwig Hallenberger2, Sara Chenguiti Fakhouri2

  • 1Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Bayern, Germany christina.bergmann@uk-erlangen.de.

Annals of the Rheumatic Diseases
|April 27, 2021
PubMed
Abstract

Insights

X-linked inhibitor of apoptosis protein (XIAP) is elevated in systemic sclerosis (SSc) and amplifies fibrosis by linking TGF-β and WNT signaling pathways. Targeting XIAP effectively reduces fibroblast activation and ameliorates SSc in mouse models.

Area of Science:

  • Molecular Biology
  • Immunology
  • Dermatology

Background:

  • X-linked inhibitor of apoptosis protein (XIAP) is a key regulator of apoptosis and cellular processes.
  • XIAP is implicated in various cancers and is an emerging therapeutic target.
  • The role of XIAP in fibrotic diseases like systemic sclerosis (SSc) remains largely unexplored.

Purpose of the Study:

  • To investigate the role of XIAP in the pathogenesis of systemic sclerosis (SSc).
  • To determine if XIAP is a potential therapeutic target for SSc.

Main Methods:

  • Quantitative PCR, immunofluorescence, and western blot were used to analyze XIAP expression in human skin samples from SSc patients, chronic graft-versus-host disease (cGvHD) patients, and healthy controls.
  • XIAP was inactivated using siRNA-mediated knockdown and pharmacological inhibition.
  • Effects of XIAP inactivation were assessed in cultured fibroblasts and in bleomycin- and topoisomerase-I-induced fibrosis mouse models, as well as in Wnt10b-transgenic mice.

Main Results:

  • XIAP expression was significantly increased in fibroblasts from SSc and sclerodermatous cGvHD skin samples compared to controls.
  • Transforming growth factor beta (TGF-β) induced XIAP expression in a SMAD3-dependent manner.
  • XIAP inactivation reduced WNT-induced fibroblast activation and collagen production, ameliorating fibrosis in multiple mouse models.
  • Profibrotic effects of XIAP were mediated via WNT/β-catenin signaling, with XIAP inactivation blocking β-catenin binding to TCF in a TLE-dependent manner.

Conclusions:

  • XIAP acts as a novel link between TGF-β/SMAD3 and WNT/β-catenin signaling pathways in fibrosis.
  • XIAP is overexpressed in SSc and cGvHD, amplifying profibrotic signaling.
  • Targeted inactivation of XIAP shows promise in inhibiting aberrant fibroblast activation and treating SSc in preclinical models.
Keywords:
fibroblastspulmonary fibrosissclerodermasystemic

More Related Videos

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

9.3K
Imaging Features of Systemic Sclerosis-Associated Interstitial Lung Disease04:44

Imaging Features of Systemic Sclerosis-Associated Interstitial Lung Disease

Published on: June 16, 2020

20.5K

Related Concept Videos

The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
9.9K
X-Inactivation01:58

X-Inactivation

The human X chromosome contains over ten times the number of genes as in the Y chromosome. Since males have only one X chromosome, and females have two, one might expect females to produce twice as many of the proteins, with undesirable results.
40.2K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
7.3K
Inheritance of Chromatin Structures03:17

Inheritance of Chromatin Structures

Epigenetics is the study of inherited changes in a cell's phenotype without changing the DNA sequences. It provides a form of memory for the differential gene expression pattern to maintain cell lineage, position-effect variegation, dosage compensation, and maintenance of chromatin structures such as telomeres and centromeres. For example, the structure and location of the centromere on chromosomes are epigenetically inherited. Its functionality is not dictated or ensured by the underlying...
6.9K