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Results shed new light on the development of chronic dermatitis

A step towards understanding chronic dermatitis

31st March 2011 - An international team of scientists led by FMLS director Ivan Dikic discovered a novel role for the protein SHARPIN in immune signalling. In today’s issue of Nature, they show how SHARPIN stimulates formation of linearized ubiquitin chains, triggering activation of a central regulator of immune responses.

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Mice deficient in the protein SHARPIN suffer from chronic proliferative dermatitis, with the underlying pathogenesis being only partly understood. The team around FMLS director Ivan Dikic now discovered a novel role of SHARPIN, which might explain the severe phenotypes observed in mice. The scientists showed that SHARPIN is part of the complex LUBAC and stimulates the formation of linear chains of the ubiquitin protein. These linear ubiquitin chains are attached to the NEMO protein, subsequently triggering activation of NF-κB, a transcription factor with a central role in the regulation of immune responses, cell proliferation and development. Absence of SHARPIN leads to dysregulation of this signalling pathway. In addition to that, the scientists also showed that SHARPIN works as an inhibitor of apoptosis via a separate signalling pathway. If SHARPIN is not functional, cell death is increased. This is a potential mechanism by which inflammatory skin lesions are formed in SHARPIN deficient mice.

Link to full research article


Press Release

A new signaling pathway of the immune system is elucidated
Ikeda et al. Nature, March 31, 2011
A new signaling pathway, important for the regulation of immune responses and inflammation, was discovered by an international team of scientists led by Professor Ivan Dikic at the Goethe University, Frankfurt, Germany. The scientists have for many years studied the involvement of ubiquitin, a universally present signaling protein in the cell. In today’s issue of the scientific journal “Nature” the research team reports their finding of a novel type of ubiquitin chains involved in the regulation of various processes within the cell.
In detail, the researchers have shown that linear ubiquitin, where ubiquitin proteins are attached to each other in a head to tail fashion, regulates signaling cascades initiated by cytokine receptors at the cell membrane. Cytokines are essential for the proper regulation of immune responses and include for example the tumor necrosis factor alpha (TNF-alpha), which is released mainly by macrophages and plays an important role in both local and body-wide inflammation. 
When a cytokine docks onto its corresponding receptor on a cell, it induces a signaling cascade, which transmits a signal to the nucleus – the centre of the cell that contains the DNA. After cytokine-induced receptor activation, the linear ubiquitin ligase complex (LUBAC), which links ubiquitin into linear head-to-tail chains, is activated at the start of this cascade. The LUBAC enzyme complex stimulates nuclear factor kappaB  (NF-kappaB), which coordinates the expression of genes important for the immune response, including the production of antibodies. However, how the molecules of this cascade function in detail and which structures interact is still under investigation.
The Dikic group solved an integral part of this puzzle by discovering that SHARPIN, a protein containing a Ubiquitin binding domain (UBD), is a key component of the linear Ubiquitin ligase complex. Using animal models, they show that a lack of Sharpin causes heavy inflammation in numerous organs and in particular the skin.  This inflammation is characterized as chronic proliferative dermatitis leading to the death of skin cells (keratinocytes) and is dependent on the TNF signaling pathways.
The research reported allows us to reshape our thinking about how chronic proliferative dermatitis arises in humans and opens new avenues of developing therapeutic interventions in the TNF-alpha signaling pathway. Moreover, this report suggests that mutations in a critical region of the linear ubiquitin ligase complex (LUBAC) is a potential source of this disease, allowing an early identification of patients that may respond well to targeted therapy. Ivan Dikic is happy to suggest that “In patients suffering from chronic proliferative dermatitis with unclear origin, it is now possible to specifically look for a mutation in LUBAC components“.

Contact for further information

Ivan Dikic
Kerstin Koch

Frankfurt Institute for Molecular Life Sciences
Goethe University Frankfurt
60438 Frankfurt am Main
Tel.: +49 (0)69 798-29489
E-mail: K.Koch@em.uni-frankfurt.de