Unravelling the Intricate Roles of FAM111A and FAM111B: From Protease-Mediated Cellular Processes to Disease Implications

Naicker, Danielle; Rhoda, Cenza; Sunda, Falone; Arowolo, Afolake

doi:10.3390/ijms25052845

Cited by 2 publications

References 79 publications

(126 reference statements)

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

Ostermann,

Luoto,

Clausen

et al. 2024

Preprint

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Interdependence between Nuclear Pore Gatekeepers and Genome Caretakers: Cues from Genome Instability Syndromes

Larizza,

Colombo

2024

IJMS

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This review starts off with the first germline homozygous variants of the Nucleoporin 98 gene (NUP98) in siblings whose clinical presentation recalls Rothmund–Thomson (RTS) and Werner (WS) syndromes. The progeroid phenotype caused by a gene associated with haematological malignancies and neurodegenerative disorders primed the search for interplay between caretakers involved in genome instability syndromes and Nuclear Pore Complex (NPC) components. In the context of basic information on NPC architecture and functions, we discuss the studies on the interdependence of caretakers and gatekeepers in WS and Hereditary Fibrosing Poikiloderma (POIKTMP), both entering in differential diagnosis with RTS. In WS, the WRN/WRNIP complex interacts with nucleoporins of the Y-complex and NDC1 altering NPC architecture. In POIKTMP, the mutated FAM111B, recruited by the Y-complex’s SEC13 and NUP96, interacts with several Nups safeguarding NPC structure. The linkage of both defective caretakers to the NPC highlights the attempt to activate a repair hub at the nuclear periphery to restore the DNA damage. The two separate WS and POIKTMP syndromes are drawn close by the interaction of their damage sensors with the NPC and by the shared hallmark of short fragile telomeres disclosing a major role of both caretakers in telomere maintenance.

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Unravelling the Intricate Roles of FAM111A and FAM111B: From Protease-Mediated Cellular Processes to Disease Implications

Cited by 2 publications

References 79 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

Interdependence between Nuclear Pore Gatekeepers and Genome Caretakers: Cues from Genome Instability Syndromes

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