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Abstract
The adenovirus type 5 (HAdV-C5) E1 transcription unit encodes regulatory proteins that are essential for viral replication and transformation. Among these, E1A and E1B-55K act as key multifunctional HAdV-C5 proteins involved in various steps of the viral replication cycle and in virus-induced cell transformation. In this context, HAdV-C5-mediated dysregulations of cellular factors such as the tumor suppressors p53 and pRB have been intensively investigated. However, cellular components of downstream events that could affect infection and viral transformation are widely unknown. We recently observed that cellular FAM111B is highly regulated in an E1A-dependent fashion. Intriguingly, previous reports suggest that FAM111B might play roles in tumorigenesis, but its exact functions are not known to date. Here, we set out to investigate the role of FAM111B in HAdV-C5 infections. We found that (i) FAM111B levels are upregulated early and downregulated late during infection, that (ii) FAM111B expression is differentially regulated, that (iii) FAM111B expression levels depend on the presence of E1B-55K and E4orf6 and that (iv) a FAM111B knockdown increases HAdV-C5 replication. Our data indicate that FAM111B acts as an anti-adenoviral host factor that is involved in host cell defense mechanisms in productive HAdV-C5 infection. Moreover, these findings suggest that FAM111B might play an important role in the host antiviral immune response that is counteracted by HAdV-C5 E1B-55K and E4orf6 oncoproteins.
Highlights
Human adenoviruses (HAdVs) are non-enveloped, linear dsDNA viruses that mostly cause asymptomatic or mild disease in younger and immunocompetent individuals
To analyze whether FAM111B transcript and protein levels are differentially regulated during HAdV-C5 infection, we infected the human lung adenocarcinoma cell line A549, that is widely used in HAdV research, with wt HAdV-C5 [16] and first investigated mRNA
FAM111B transcript levels increased at 16–24 h post infection (h p.i.) compared to mock (Figure 1A) but interestingly dropped at 48 h p.i. (Figure 1A). These results indicate that FAM111B is regulated at the transcriptional level in response to HAdV-C5 infection, implying that FAM111B might belong to the family of immediate early response genes activated upon HAdV infection
Summary
Human adenoviruses (HAdVs) are non-enveloped, linear dsDNA viruses that mostly cause asymptomatic or mild disease in younger and immunocompetent individuals. HAdV infections of immunocompromised patients or patients with pre-existing respiratory or cardiac conditions can cause severe disease courses and are serious health issues [1]. It is important to thoroughly study basic mechanisms of HAdV infection as well as the interplay between HAdV gene products and host immunity. The exact function of FAM111B, the second and last member of the “family with sequence similarity 111” gene family, is widely unknown. Though, a recent study demonstrated that FAM111B co-precipitates with HAdV-C5 E1B-55K [2]. FAM111B contains a predicted trypsin-like cysteine/serine peptidase domain, comprising of two subdomains connected by a linker region. Three specific alterations within the linker region were previously found to induce hereditary fibrosing poikiloderma [3].
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