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Unusual iron-sulfur cluster maturation of the antiviral radical SAM protein viperin
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. (Anna Överby)
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(English)Manuscript (preprint) (Other academic)
Keyword [en]
Viperin, Iron-sulphur cluster, CIA1, CIA2A, CIA2B and MMS19
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:umu:diva-128726OAI: oai:DiVA.org:umu-128726DiVA: diva2:1055965
Available from: 2016-12-13 Created: 2016-12-13 Last updated: 2016-12-14
In thesis
1. Viperin, a multifunctional radical SAM enzyme: biogenesis and antiviral mechanisms
Open this publication in new window or tab >>Viperin, a multifunctional radical SAM enzyme: biogenesis and antiviral mechanisms
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, interferon-inducible) is an interferon-induced antiviral protein. It has three distinct functional domains: the N-terminal domain, the radical SAM (S-adenosylmethionine) domain for binding iron-sulphur cluster, and the C-terminus domain. Viperin has a broad antiviral effect, and is also involved in the immune response signalling. However, the function and antiviral mechanism of viperin are still not well characterized. Thus the overall aim of the thesis was to investigate and better understand the function of viperin and its antiviral mechanism by identifying the cellular network of interaction partners. Affinity purification and mass spectrometry analysis were used to identify cellular proteins that interact with viperin.

CIA1 (also known as CIAO1), a factor involved in loading of iron-sulphur (Fe/S) cluster was identified and confirmed to interact at the C-terminus of viperin. It was also seen that the C-terminal domain and the functional SAM domain of viperin was essential for loading the Fe/S cluster onto viperin. On a closer look at the biogenesis of viperin, we identified and confirmed viperin interaction with CIA2A, CIA2B, (also known as FAM96A and FAM96B respectively) and MMS19, which are other factors involved in the transfer of Fe/S clusters onto cytosolic Fe/S apo-proteins. Surprisingly, MMS19, which has been shown to act as an adapter protein for other Fe/S proteins, only interacted indirectly and was not required for transferring the Fe/S cluster. Similarly, the interaction of viperin with both the isoforms of CIA2 was interesting, but the role they play in viperin biogenesis and antiviral function is still not clear and requires further investigation.

Study of the antiviral action of viperin against tick-borne encephalitis virus (TBEV) showed that the activity of the SAM domain is essential for the strong inhibition of genome replication of TBEV. Furthermore, viperin also affects the assembly and release of TBEV. Viperin interacts with GBF1 and downregulates its activity, thus preferentially inducing the secretion of viral capsid protein from the cell, and therefore disrupting the formation of infectious virus particles. The N-terminal domain of viperin is important for its effect on assembly and release.

In summary, this work contributes to our general understanding of viperin biogenesis in the cell regarding the loading of Fe/S cluster onto viperin. It also addresses the importance of the different domains for its antiviral function against TBEV. Finally, mass spectrometry and viperin interactome analysis implicate many other interesting cellular pathways or processes that might give us a better understanding of viperin’s function and antiviral mechanism. 

Place, publisher, year, edition, pages
Umeå: Umeå University, 2016. 68 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1869
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-128754 (URN)978-91-7601-627-5 (ISBN)
Public defence
2017-01-20, Room E04_R1, Building 6A, University Hospital of Umeå, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2016-12-16 Created: 2016-12-14 Last updated: 2016-12-16Bibliographically approved

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