Differential Regulation of Cellular FAM111B by Human Adenovirus C Type 5 E1 Oncogenes

Ip, Wing Hang; Wilkens, Britta; Solomatina, Anastasia I.; Martin, Judith A.; Melling, Michael; Hidalgo, Paloma; Bertzbach, Luca D.; Speiseder, Thomas; Dobner, Thomas

doi:10.3390/v13061015

Cited by 6 publications

(7 citation statements)

References 29 publications

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“…FAM111B is a trypsin-like cysteine/serine peptidase conserved in primates but absent in rodents (17). Interestingly, FAM111B has been described as a restriction factor for human adenovirus type 5 (Ad5) (18) whereas its paralog, FAM111A is a host range factor for SV40 and orthopoxviruses (19,20). We therefore included FAM111A in our analysis, as it is also downregulated in our transcriptome analysis, but with a lower log2 fold change of -0.92.…”

Section: E2f3 Is a Major Regulator Of Fam111a And Fam111b During Mcmv...mentioning

confidence: 99%

“…While FAM111A is a restriction factor for host range mutants of SV40 and orthopoxviruses (19,20), FAM111B is a restriction factor for Ad5 (18). To identify whether one of these two proteins functions as an MCMV restriction factor, we generated recombinant MCMVs encoding shRNAs specific for FAM111A (MCMV A-sh) or FAM111B (MCMV B-sh), using the same method as described above for CCNE2 (…”

Section: E2f3 Is a Major Regulator Of Fam111a And Fam111b During Mcmv...mentioning

confidence: 99%

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E2F3-dependent activation of FAM111B restricts mouse cytomegalovirus replication in primate cells

Ostermann,

Luoto,

Clausen

et al. 2024

Preprint

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Cytomegaloviruses are highly species-specific as they replicate only in cells of their own or a closely related species. For instance, human cytomegalovirus cannot replicate in rodent cells, and mouse cytomegalovirus (MCMV) cannot replicate in human and monkey cells. However, the mechanisms underlying the host species restriction remain poorly understood. We have previously shown that passaging MCMV in human retinal pigment epithelial cells allows the virus to replicate to high titers in these cells due to the accumulation of adaptive mutations, such as loss-of-function mutations in the viral M117 gene. The M117 protein interacts with E2F transcription factors and activates E2F-dependent transcription. Here we show that activation of E2F3 is primarily responsible for MCMV’s inability to replicate in human cells. By transcriptome analysis, we identified two E2F3-induced serine proteases, FAM111A and FAM111B, as potential host restriction factors. By using shRNA-mediated gene knockdown and CRISPR/Cas9-mediated gene knockout, we demonstrated that FAM111B, but not its paralog FAM111A, suppresses MCMV replication in human and rhesus macaque cells. By immunofluorescence, we detected FAM111B predominantly in the nucleus of infected cells with enrichment in viral replication compartments, suggesting that it might play a role during viral replication. The fact that the FAM111B gene is conserved in primates but absent in rodents suggests that MCMV has not evolved to evade or counteract this restriction factor, which is not present in its natural host.ImportanceViruses must counteract host cell defenses to facilitate viral replication. Viruses with a narrow host range, such as the cytomegaloviruses, are unable to counteract cellular defenses in cells of a foreign species. However, little is known about the cellular host range factors restricting cytomegalovirus replication. Here we show that MCMV induces the expression of the FAM111 proteases and that FAM111B, but not FAM111A that has previously been shown to restrict the replication of polyomavirus and orthopoxvirus host range mutants, acts as a cellular factor suppressing MCMV replication in human and rhesus monkey cells. The identification of FAM111B as a host range factor should provide new insight into the physiological functions of this poorly characterized protein.

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Section: E2f3 Is a Major Regulator Of Fam111a And Fam111b During Mcmv...mentioning

confidence: 99%

Section: E2f3 Is a Major Regulator Of Fam111a And Fam111b During Mcmv...mentioning

confidence: 99%

E2F3-dependent activation of FAM111B restricts mouse cytomegalovirus replication in primate cells

Ostermann,

Luoto,

Clausen

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Furthermore, FAM111B levels rise early and decrease late during human adenovirus infection. 13 However, the mechanisms underlying FAM111B expression and function in ovarian cancer remain unknown. Herein, FAM111B expressions were significantly upregulated in ovarian cancer tissues and various ovarian cancer cell lines.…”

Section: Impact Statementmentioning

confidence: 99%

“…10 –12 Furthermore, FAM111B levels rise early and decrease late during human adenovirus infection. 13 However, the mechanisms underlying FAM111B expression and function in ovarian cancer remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Silencing of FAM111B inhibits tumor growth and promotes apoptosis by decreasing AKT activity in ovarian cancer

Wang

et al. 2023

Exp Biol Med (Maywood)

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Ovarian cancer is the most lethal gynecological tumor in women worldwide. FAM111B (family with sequence similarity 111 member B) is an oncoprotein associated with multiple cancers, but its biological functions in ovarian cancer remain elusive. In this study, FAM111B was overexpressed in ovarian cancer tissues and cell lines. Functional studies in vitro revealed that silencing of FAM111B inhibited ovarian cancer cell proliferation, invasion, and migration, as well as increased cell apoptosis. Furthermore, FAM111B silencing arrested the ovarian cancer cell cycle at the G1/S phase. Furthermore, western blot assays demonstrated that silencing of FAM111B resulted in downregulation of phospho-AKT (p-AKT) protein expression, as well as upregulation of p53 and caspase-1 protein expression. The xenograft animal model of ovarian cancer demonstrated that FAM111B silencing inhibited tumor growth, enhanced cell apoptosis, and inhibited Ki-67 and proliferating cell nuclear antigen (PCNA) protein expression in vivo. Conversely, the overexpression of FAM111B exhibited opposite effects on the ovarian cancer xenograft. It was previously established that inactivating AKT inhibited ovarian cancer progression. This study found that silencing of FAM111B inhibits tumor growth and promotes apoptosis by decreasing AKT activity in ovarian cancer. Caspase-1 and p53 signaling also influenced the function of FAM111B in SKOV3 cells. Collectively, our results demonstrate that silencing of FAM111B is a potential therapeutic strategy against ovarian cancer.

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“…In contrast to FAM111A, FAM111B does not interact with SV40 LT and has not been implicated in cellular protection from SV40 ( Fine et al, 2012 ). However, a recent study showed that FAM111B is upregulated after infection with human adenovirus and functions as a host restriction factor ( Ip et al, 2021 ), suggesting that FAM111B might be an antiviral factor with different specificity.…”

Section: Fam111b: a Paralog Of Fam111amentioning

confidence: 99%

Functions and evolution of FAM111 serine proteases

Welter

Machida

2022

Front. Mol. Biosci.

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Proteolysis plays fundamental and regulatory roles in diverse cellular processes. The serine protease FAM111A (FAM111 trypsin-like peptidase A) emerged recently as a protease involved in two seemingly distinct processes: DNA replication and antiviral defense. FAM111A localizes to nascent DNA and plays a role at the DNA replication fork. At the fork, FAM111A is hypothesized to promote DNA replication at DNA-protein crosslinks (DPCs) and protein obstacles. On the other hand, FAM111A has also been identified as a host restriction factor for mutants of SV40 and orthopoxviruses. FAM111A also has a paralog, FAM111B, a serine protease with unknown cellular functions. Furthermore, heterozygous missense mutations in FAM111A and FAM111B cause distinct genetic disorders. In this review, we discuss possible models that could explain how FAM111A can function as a protease in both DNA replication and antiviral defense. We also review the consequences of FAM111A and FAM111B mutations and explore possible mechanisms underlying the diseases. Additionally, we propose a possible explanation for what drove the evolution of FAM111 proteins and discuss why some species have two FAM111 proteases. Altogether, studies of FAM111 proteases in DNA repair, antiviral defense, and genetic diseases will help us elucidate their functions and the regulatory mechanisms.

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Differential Regulation of Cellular FAM111B by Human Adenovirus C Type 5 E1 Oncogenes

Cited by 6 publications

References 29 publications

E2F3-dependent activation of FAM111B restricts mouse cytomegalovirus replication in primate cells

E2F3-dependent activation of FAM111B restricts mouse cytomegalovirus replication in primate cells

Silencing of FAM111B inhibits tumor growth and promotes apoptosis by decreasing AKT activity in ovarian cancer

Functions and evolution of FAM111 serine proteases

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