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Infection research
08.06.2018

Adenovirus hijacks cellular waste removal system

Human adenoviruses (HAdV) are able to seize control of the central waste disposal system of cells and reprogram it to their own advantage. As researchers from the Helmholtz Zentrum München report in the Journal of Virology, such a hostile takeover can have numerous repercussions, including programmed cell death and uncontrolled cellular division.

Adenoviruses have been research objects for more than 60 years, and many important findings in the fields of cell biology and cancer development have emerged from such work. “However, the mechanisms that account for the pathogenicity of these viruses are still not understood and need to be investigated as a matter of urgency, as no specific pharmacological intervention strategies against HAdV infections are currently known,” explains PD Dr. Sabrina Schreiner, head of the Antiviral Defense of DNA Viruses Working Group at the Institute of Virology of Helmholtz Zentrum München and the Technical University of Munich (TUM).

In their current work, her team, in cooperation with a team of scientists led by Dr. Kamyar Hadian of the Institute of Molecular Toxicology and Pharmacology at Helmholtz Zentrum München, has gained new insights into the mechanisms of infection. “We were able to show that the cellular protein RNF4 plays a key role in the infection process,” explains study leader Schreiner. “RNF4 is a ubiquitin ligase, a protein that tags other molecules for disposal.”

Overcoming antiviral defenses

As the paper explains, RNF4 also occurs naturally in the host cell and is merely commandeered by the virus during an infection. “To do so, the virus produces a protein called E1B-55K, which binds to RNF4 and causes it to break down antivirus proteins,” explains lead author and doctoral student Sarah Müncheberg. The researchers demonstrated this specifically with the antiviral protein Daxx (death domain-associated protein). According to the authors, such an intervention in the cellular metabolism can lead to numerous long-term consequences, such as destruction of the cell by programmed cell death, as well as the elimination of DNA repair processes, thus contributing to the virus-mediated development of cancer cells.

 “In recent years, attention has again focused on HAdV,” says Schreiner, describing the relevance of the results: “New highly pathogenic adenovirus strains have been detected in China, the US and Europe. Unlike earlier strains, they not only affect immunocompromized patients but, for the first time, also lead to the development of life-threatening pneumonia in healthy individuals.” She and her team therefore hope that their findings will lead to new therapeutic approaches.

Further information

Background:

Doctoral students Christina Weiss, Jara Brenke and Sawinee Masser are participants in the doctoral education program Helmholtz Graduate School Environmental Health, HELENA for short.

Sabrina Schreiner has already received the Jürgen Wehland Award for her research into the virus-host interactions of human adenoviruses.


Original publication:
Müncheberg, S. et al. (2018): E1B-55K mediated regulation of RNF4 STUbL promotes HAdV gene expression. Journal of Virology, DOI: 10.1128/JVI.00164-18

As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,300 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. 

Technical University of Munich (TUM) is one of Europe’s leading research universities, with more than 500 professors, around 10,000 academic and non-academic staff, and 40,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, com-bined with economic and social sciences. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, TUM regularly places among the best universities in Germany.