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  • Crohn's disease

News about the creation: Missing Link found

    • Gastroenterology and Hepatology
    • General Internal Medicine
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  • 3 minute read

Little is known about the genesis of Crohn’s disease. A look at the TGF-β signaling pathway and the role of CYLD in its inhibition recently provided new insights.

Despite intensive research, the mechanisms of development of the chronic inflammatory bowel disease Crohn’s disease are not clear. The pathogenesis is closely associated with impaired TGF-β signaling. In Crohn’s patients, there is also a high expression of the protein CYLD, which is associated with the intestinal disease. However, whether and – if so – how both observations are related was unclear until now. A recent study sheds light on the issue.

What do you know?

The cytokine TGF-β (“transforming growth factor beta”) regulates various cell responses such as differentiation, proliferation, apoptosis and oncogenesis. How exactly varies depending on the context. TGF-β has anti-inflammatory and immunosuppressive effects, among others. By binding to serine threonine kinases, it phosphorylates certain intracellular R-SMADs, which then migrate as a complex to the nucleus where they inhibit or promote the expression of specific genes.

This signal transduction is influenced by SMAD7. SMAD7 blocks the anti-inflammatory messenger TGF-β1, resulting in an enhanced immune response. In a sense, the protein thus acts as a counterpart of TGF-β. Usually it occurs only in small quantities. Larger amounts have been found in inflammatory bowel disease.

CYLD also plays an important role. The enzyme encodes tumor suppressor proteins. In mutated form, it manifests as familial cylindromatosis. Initially discovered as a tumor suppressor, variant CYLD mutations are now associated with Crohn’s disease. This is because CYLD modulates SMAD7.

Splice shape of CYLD as a key

The study, led by Dr. Yilang Tang and Dr. Sonja Reissig of the Institute of Molecular Medicine at the University of Mainz, examined colon cells from Crohn’s patients and from subjects without inflammatory bowel disease. The aim was to understand the interaction of CYLD and TGF-β signaling pathway.

Subsequently, the research team saw previous observations confirmed: Biopsies from Crohn’s patients showed greatly increased CYLD expressions as well as impaired TGF-β signaling compared to healthy populations. In addition, the molecular physicians discovered who is responsible for the disruption of the signaling pathway: an alternative splice form of CYLD.

Splicing is a process in gene transcription in which the undescribed gene segment (intron) is separated from the encoded one (exon). This process takes place according to different patterns, which is why alternative splice shapes can occur. While CYLD, together with SMAD3, promotes TGF-β signaling, sCYLD, a short splice form of CYLD, inhibits this process by increasing activation of SMAD7. The change in signal transduction leads to hyperactivity of effector T cells. The mechanism was proven in animal experiments. Analogous to the patient data, mice overexpressing sCYLD and SMAD7 developed severe spontaneous colitis. The level of sCYLD and SMAD7 correlated with the severity of the disease.

The search continues

The study results provide an important contribution to the understanding of the pathogenesis of Crohn’s disease. They suggest that CYLD is directly related to Crohn’s disease and direct the focus to the CYLD splicing mechanism. Its regulation is therapeutically relevant. But further studies with a larger patient corpus are needed to evaluate this possibility. The importance of the CYLD splicing mechanism also needs further investigation with regard to other inflammatory bowel diseases.

Source: Tang Y, et al: Alternative Splice Forms of CYLD Mediate Ubiquitination of SMAD7 to Prevent TGFB Signaling and Promote Colitis. Gastroenterol 2019; 156: 692-707.

 

 

GP PRACTICE 2019; 14(4): 35

Autoren
  • Barbara Hug
Publikation
  • HAUSARZT PRAXIS
Related Topics
  • Bowel disease
  • Crohn's disease
  • tgf-beta
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