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Human adenovirus core protein pVII influences mitochondrial DNA dynamics and expression of the pro-inflammatory cytokine IL-32
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0003-1344-3962
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0002-0561-367x
(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-389804OAI: oai:DiVA.org:uu-389804DiVA, id: diva2:1339326
Available from: 2019-07-29 Created: 2019-07-29 Last updated: 2019-07-29
In thesis
1. Human adenovirus – host cell interplay: The role of the cellular zinc finger proteins and mitochondrial DNA
Open this publication in new window or tab >>Human adenovirus – host cell interplay: The role of the cellular zinc finger proteins and mitochondrial DNA
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human adenovirus (HAdV) is an abundant DNA virus with significant clinical relevance since it cauces a variety of respiratory, ocular, and gastrointestinal diseases. It is also intensively used as a therapeutic tool to treat cancers and to boost immune responses. In order to achieve a better control over the HAdV epidemiology and improved utilization for clinical applications, it is crucial to understand the molecular interaction between the host cell and HAdV.

The aim of the current thesis is to delineate the molecular interactions between HAdV type 5 (HAdV-C5) protein VII (pVII), two cellular zinc finger proteins (MKRN1, ZNF622)  and mitochondrial DNA (mtDNA). In paper I, we have identified MKRN1 as one of the novel pVII-interacting proteins. Surprisingly, endogenous MKRN1 protein is down-regulated in the HAdV-infected cells due to its proteasomal degradation. Further, the pVII(wt) promoted  MKRN1 self-ubiquitination, which may explain the overall instability of the MKRN1 protein in the infected cells. In addition, we show that the MKRN1 protein is also down-regulated in measles virus- and vesicular stomatitis virus-infected cells. In paper II, we report that the cellular ZNF622 protein interacts with the pVII protein. Intriguingly, ZNF622 expression was enhanced in HAdV-C5-infected cells, implying its anti-viral role. Surprisingly, lack of the ZNF622 protein significantly enhanced formation of the infectious HAdV-C5 virions. Finally, we propose a model how the ZNF622/NPM1/pVII protein complex regulates the pVII protein binding to viral DNA. In paper III, we report that HAdV-C5 infection enhanced mtDNA release into cytosol. The enhanced mtDNA release can be partially explained by accumulation of the pVII protein since its down-regulation diminished mtDNA release into cyotosol. We also report pVII-regulated gene expression profile and show that cellular cytokine IL-32 mRNA accumulates in response to the pVII protein expression.

Collectively, in this thesis we provide molecular characterization how two cellular zinc finger proteins (MKRN1 and ZNF622) and mtDNA behave in the context of lytic HAdV-C5 infection. The ZNF622 may act as a bona fide anti-viral factor blocking infectious virion formation via targeting the essential viral core protein pVII. The MKRN1 protein is efficiently eliminated in the infected cells, highlighting the essence of HAdV-C5-controlled proteasome. Finally, dynamical change of mtDNA induced by HAdV-C5 infection, might initiate a novel signaling pathway beneficial for the cells or the viruses.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 61
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1583
Keywords
Adenovirus, Protein VII, Ubiquitination, Chromatin remodeling, Mitochondria
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-389805 (URN)978-91-513-0696-4 (ISBN)
Public defence
2019-09-05, C8:305, Biomedical Centrum (BMC), Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2019-08-15 Created: 2019-07-29 Last updated: 2019-09-17

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Mun, KwangcholInturi, RavitejaPunga, Tanel

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