A Novel Function of Human Pumilio Proteins in Cytoplasmic Sensing of Viral Infection

Narita, Ryo; Takahasi, Kiyohiro; Murakami, Etsu; Hirano, Emi; Yamamoto, Seiji; Yoneyama, Mitsutoshi; Kato, Hiroki; Fujita, Takashi

doi:10.1371/journal.ppat.1004417

Cited by 51 publications

(49 citation statements)

References 49 publications

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“…Additionally, immunoprecipition of endogenous PUM proteins resulted in highly significant enrichment of endogenous NORAD (Figure S5C). Consistent with these data, both NORAD (Figure S4D, E) as well as PUM1/PUM2 (Morris et al, 2008; Narita et al, 2014; Ponten et al, 2008) are predominantly localized to the cytoplasm.…”

Section: Resultssupporting

confidence: 84%

Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins

Lee

Kopp

Chang

et al. 2016

Cell

731

778

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SUMMARY Long noncoding RNAs (lncRNAs) have emerged as regulators of diverse biological processes. Here we describe the initial functional analysis of a poorly characterized human lncRNA (LINC00657) that is induced after DNA damage, which we termed Noncoding RNA Activated by DNA Damage or NORAD. NORAD is highly conserved and abundant, with expression levels of approximately 500–1,000 copies per cell. Remarkably, inactivation of NORAD triggers dramatic aneuploidy in previously karyotypically-stable cell lines. NORAD maintains genomic stability by sequestering PUMILIO proteins, which repress the stability and translation of messenger RNAs to which they bind. In the absence of NORAD, PUMILIO proteins drive chromosomal instability by hyperactively repressing mitotic, DNA repair, and DNA replication factors. These findings introduce a mechanism that regulates the activity of a deeply conserved and highly dosage-sensitive family of RNA binding proteins and reveal unanticipated roles for a lncRNA and PUMILIO proteins in the maintenance of genomic stability.

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Section: Resultssupporting

confidence: 84%

Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins

Lee

Kopp

Chang

et al. 2016

Cell

731

778

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“…Alternatively, some have been shown to participate in antiviral responses early during HSV-1 infection as either positive regulation (e.g. PUM2) (37) or negative regulation (XIAP, SP1) (38). Other proteins that follow the same trend as known viral degradation targets over the time course may represent potential novel candidates for degradation by HSV-1.…”

Section: Fig 1 Proteome Characterization During Hsv-1 Infection By mentioning

confidence: 99%

Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection

Kulej

Avgousti

Sidoli

et al. 2017

Molecular & Cellular Proteomics

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Herpes simplex virus (HSV-1) lytic infection results in global changes to the host cell proteome and the proteins associated with host chromatin. We present a system level characterization of proteome dynamics during infection by performing a multi-dimensional analysis during HSV-1 lytic infection of human foreskin fibroblast (HFF) cells. Our study includes identification and quantification of the host and viral proteomes, phosphoproteomes, chromatin bound proteomes and post-translational modifications (PTMs) on cellular histones during infection. We analyzed proteomes across six time points of virus infection (0, 3, 6, 9, 12 and 15 h post-infection) and clustered trends in abundance using fuzzy c-means. Globally, we accurately quantified more than 4000 proteins, 200 differently modified histone peptides and 9000 phosphorylation sites on cellular proteins. In addition, we identified 67 viral proteins and quantified 571 phosphorylation events (465 with high confidence site localization) on viral proteins, which is currently the most comprehensive map of HSV-1 phosphoproteome. We investigated chromatin bound proteins by proteomic analysis of the high-salt chromatin fraction and identified 510 proteins that were significantly different in abundance during infection. We found 53 histone marks significantly regulated during virus infection, including a steady increase of histone H3 acetylation (H3K9ac and H3K14ac). Our data provide a resource of unprecedented depth for human and viral proteome dynamics during infection. Collectively, our results indicate that the proteome composition of the chromatin of HFF cells is highly affected during HSV-1 infection, and that phosphorylation events are abundant on viral proteins. We propose that our epi-proteomics approach will prove to be important in the characterization of other model infectious systems that involve changes to chromatin composition. Molecular & Cellular Proteomics 16: 10.1074/mcp.M116.065987, S92-S107, 2017. Herpes simplex virus (HSV-1)1 leads to a contagious and persistent infection that affects about 95% of the human population. The HSV-1 genome is a double-stranded DNA molecule that replicates in the host cell nucleus (1). HSV-1 initially infects epithelial cells as a lytic infection, and then enters peripheral neurons where it establishes latency (2, 3). Processes such as viral transcription, viral DNA synthesis, virion assembly and DNA packaging take place in discrete virus-induced structures within the nucleus called replication compartments (1, 4). These processes are temporally regulated by the viral cascades of immediate-early (IE), early (E), and late (L) gene expression. The IE proteins are primarily responsible for counteracting intrinsic host defenses and for activating expression of early-phase genes (1). Early viral pro-

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“…Conversely, Ser/Thr phosphorylation (induced by protein kinase C and casein kinase II), Lys48-linked polyubiquitination, and removal of K63-linked polyubiquitin by several deubiquitinating enzymes (CYLD, USP3 and USP21) inhibit RIG-I activation (reviewed in detail in [2]). Furthermore, it was recently reported that the RNA-binding activity of LGP2 is regulated by Pumilio proteins (PUM1/2) [20]. …”

Section: Cytosolic Sensing Of Vrnamentioning

confidence: 99%

Intracellular detection of viral nucleic acids

Sparrer

Gack

2015

Current Opinion in Microbiology

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Successful clearance of a microbial infection depends on the concerted action of both the innate and adaptive arms of the immune system. Accurate recognition of an invading pathogen is the first and most crucial step in eliciting effective antimicrobial defense mechanisms. In recent years, remarkable progress has been made towards understanding the molecular details of how the innate immune system recognizes microbial signatures, commonly called pathogen-associated molecular patterns (PAMPs). For viral pathogens, nucleic acids — both viral genomes and viral replication products — represent a major class of PAMPs that trigger antiviral host responses via activation of germline-encoded innate immune receptors. Here we summarize recent advances in intracellular innate sensing mechanisms of viral RNA and DNA.

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A Novel Function of Human Pumilio Proteins in Cytoplasmic Sensing of Viral Infection

Cited by 51 publications

References 49 publications

Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins

Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins

Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection

Intracellular detection of viral nucleic acids

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