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Conservation of the transcriptional and post-­transcriptional activities of serotype-­specific adenovirus L4 proteins
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Göran Akusjärvi)ORCID iD: 0000-0002-0797-8007
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. (Göran Akusjärvi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-238482OAI: oai:DiVA.org:uu-238482DiVA: diva2:771134
Available from: 2014-12-12 Created: 2014-12-12 Last updated: 2015-03-09
In thesis
1. Functional Characterization of the Evolutionarily Conserved Adenoviral Proteins L4-22K and L4-33K
Open this publication in new window or tab >>Functional Characterization of the Evolutionarily Conserved Adenoviral Proteins L4-22K and L4-33K
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Regulation of adenoviral gene expression is a complex process directed by viral proteins controlling a multitude of different activities at distinct phases of the virus life cycle. This thesis discusses adenoviral regulation of transcription and splicing by two proteins expressed at the late phase: L4-22K and L4-33K. These are closely related with a common N-terminus but unique C-terminal domains. The L4-33K protein is an alternative RNA splicing factor inducing L1-IIIa mRNA splicing, while L4-22K is stimulating transcription from the major late promoter (MLP). The L4-33K protein contains a tiny RS-repeat in its unique C-terminal end that is essential for the splicing enhancer function of the protein. Here we demonstrate that the tiny RS-repeat is required for localization of the protein to the nucleus and viral replication centers. Further, we describe an auto-regulatory loop where L4-33K enhances splicing of its own intron. The preliminary characterization of the responsive RNA-element suggests that it differs from the previously defined L4-33K-responsive element activating L1-IIIa mRNA splicing.

L4-22K lacks the ability to enhance L1-IIIa splicing in vivo, and here we show that the protein is defective in L1-IIIa or other late pre-mRNA splicing reactions in vitro. Interestingly, we found a novel function for the L4-22K and L4-33K proteins as regulators of E1A alternative splicing. Both proteins selectively upregulated E1A-10S mRNA accumulation in transfection experiments, by a mechanism independent of the tiny RS-repeat.

Although L4-22K is reported to be an MLP transcriptional enhancer protein, here we show that L4-22K also functions as a repressor of MLP transcription. This novel activity depends on the integrity of the major late first leader 5’ splice site. The model suggests that at low concentrations L4-22K activates MLP transcription while at high concentrations L4-22K represses transcription.

So far, characterizations of the L4-22K and L4-33K proteins have been limited to human adenoviruses 2 or 5 (HAdV-2/5). We expanded our experiments to include HAdV-3, HAdV-4, HAdV-9, HAdV-11 and HAdV-41. The results demonstrated that the transcription- or splicing-enhancing properties of L4-22K and L4-33K, respectively, are evolutionarily conserved and non-overlapping. Thus, the sequence-based conservation is mirrored by the functions, as expected for functionally important proteins.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1062
Keyword
L4-22K, L4-33K, RNA, splicing, adenovirus, nuclear localization, replication, transcription, evolution, SR protein, MLP, promoter, E1A, serotypes
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-238487 (URN)978-91-554-9132-1 (ISBN)
Public defence
2015-02-13, C8:301, BMC, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-01-23 Created: 2014-12-12 Last updated: 2015-03-09

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Östberg, Sara

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