Human IFIT proteins inhibit lytic replication of KSHV: A new feed-forward loop in the innate immune system

Li, Dajiang; Swaminathan, Sankar

doi:10.1371/journal.ppat.1007609

Cited by 36 publications

(47 citation statements)

References 65 publications

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“…4C and D). As a control, we tested IFIT1 binding to the U6 snRNA (RNU6), which has a gamma-monomethyl 5= cap, and we found, similarly to results reported previously by others (44), that IFIT1 did not bind this RNA. We next tested if CMTR1-regulated ISGs contained RNA elements that could dictate their sensitivity to translational repression by IFIT1.…”

Section: Resultssupporting

confidence: 75%

The mRNA Cap 2′- O -Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes

Williams

Gokhale

Snider

et al. 2020

mSphere

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Type I interferons (IFN) initiate an antiviral state through a signal transduction cascade that leads to the induction of hundreds of IFN-stimulated genes (ISGs) to restrict viral infection. Recently, RNA modifications on both host and viral RNAs have been described as regulators of infection. However, the impact of host mRNA cap modifications on the IFN response and how this regulates viral infection are unknown. Here, we reveal that CMTR1, an ISG that catalyzes 2′-O-methylation of the first transcribed nucleotide in cellular mRNA (Cap 1), promotes the protein expression of specific ISGs that contribute to the antiviral response. Depletion of CMTR1 reduces the IFN-induced protein levels of ISG15, MX1, and IFITM1, without affecting their transcript abundance. However, CMTR1 depletion does not significantly affect the IFN-induced protein or transcript abundance of IFIT1 and IFIT3. Importantly, knockdown of IFIT1, which acts with IFIT3 to inhibit the translation of RNAs lacking Cap 1 2′-O-methylation, restores protein expression of ISG15, MX1, and IFITM1 in cells depleted of CMTR1. Finally, we found that CMTR1 plays a role in restricting RNA virus replication, likely by ensuring the expression of specific antiviral ISGs. Taken together, these data reveal that CMTR1 is required to establish an antiviral state by ensuring the protein expression of a subset of ISGs during the type I IFN response. IMPORTANCE Induction of an efficient type I IFN response is important to control viral infection. We show that the host 2′-O-methyltransferase CMTR1 facilitates the protein expression of ISGs in human cells by preventing IFIT1 from inhibiting the translation of those mRNAs lacking cap 2′-O-methylation. Thus, CMTR1 promotes the IFN-mediated antiviral response.

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Section: Resultssupporting

confidence: 75%

The mRNA Cap 2′- O -Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes

Williams

Gokhale

Snider

et al. 2020

mSphere

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“…However, we found that IFIT1 bound to both the CMTR1-regulated and -nonregulated transcripts following CMTR1 depletion ( Figure 4C-D ). As a control, we tested IFIT1 binding to the U6 snRNA ( RNU6 ), which has a gamma-monomethyl 5’ cap, and we found, similar to others, that IFIT1 did not bind this RNA (44). We next tested if CMTR1-regulated ISGs contained RNA elements that could dictate their sensitivity to translational repression by IFIT1.…”

Section: Resultssupporting

confidence: 60%

The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

Williams

Gokhale

Snider

et al. 2020

Preprint

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AbstractType I interferons (IFN) initiate an antiviral state through a signal transduction cascade that leads to the induction of hundreds of IFN-stimulated genes (ISGs) to restrict viral infection. Recently, RNA modifications on both host and viral RNAs have been described as regulators of infection. However, the impact of host mRNA cap modifications on the IFN response and how this regulates viral infection is unknown. Here, we reveal that CMTR1, an ISG that catalyzes 2’O methylation of the first transcribed nucleotide in cellular mRNA (Cap 1), promotes the protein expression of specific ISGs that contribute to the antiviral response. Depletion of CMTR1 reduces the IFN-induced protein levels of ISG15, MX1, and IFITM1, without affecting their transcript abundance. However, CMTR1 depletion does not significantly affect the IFN-induced protein or transcript abundance of IFIT1 and IFIT3. Importantly, knockdown of IFIT1, which acts with IFIT3 to inhibit the translation of RNAs lacking Cap 1 2’O methylation, restores protein expression of ISG15, MX1, and IFITM1 in cells depleted of CMTR1. Finally, we found that CMTR1 plays a role in restricting RNA virus replication, likely by ensuring the expression of specific antiviral ISGs. Taken together, these data reveal that CMTR1 is required to establish an antiviral state by ensuring the protein expression of a subset of ISGs during the type I IFN response.ImportanceInduction of an efficient type I IFN response is important to control viral infection. We show that the host 2’O methyltransferase CMTR1 facilitates the protein expression of ISGs in human cells by preventing IFIT1 from inhibiting the translation of these mRNAs lacking cap 2’O methylation. Thus, CMTR1 promotes the IFN-mediated antiviral response.

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“…These proteins upregulate IFNβ and 2′,5′-oligoadenylate synthetase (OAS) proteins to promote the degradation of viral RNA. Loss of IFIT1, IFIT2, and IFIT3 leads to broad increases in lytic gene expression and subsequent virion production, implicating them in control of KSHV latency [ 45 ]. Interferon stimulation also changes cellular patterns of posttranslational modifications, particularly through the induction of interferon-stimulated gene 15 (ISG15) conjugation.…”

Section: Mechanisms Regulating the Maintenance Of Kshv Latencymentioning

confidence: 99%

Regulation of KSHV Latency and Lytic Reactivation

Broussard

Damania

2020

Viruses

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Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with three malignancies— Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). Central to the pathogenesis of these diseases is the KSHV viral life cycle, which is composed of a quiescent latent phase and a replicative lytic phase. While the establishment of latency enables persistent KSHV infection and evasion of the host immune system, lytic replication is essential for the dissemination of the virus between hosts and within the host itself. The transition between these phases, known as lytic reactivation, is controlled by a complex set of environmental, host, and viral factors. The effects of these various factors converge on the regulation of two KSHV proteins whose functions facilitate each phase of the viral life cycle—latency-associated nuclear antigen (LANA) and the master switch of KSHV reactivation, replication and transcription activator (RTA). This review presents the current understanding of how the transition between the phases of the KSHV life cycle is regulated, how the various phases contribute to KSHV pathogenesis, and how the viral life cycle can be exploited as a therapeutic target.

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Human IFIT proteins inhibit lytic replication of KSHV: A new feed-forward loop in the innate immune system

Cited by 36 publications

References 65 publications

The mRNA Cap 2′- O -Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes

The mRNA Cap 2′- O -Methyltransferase CMTR1 Regulates the Expression of Certain Interferon-Stimulated Genes

The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

Regulation of KSHV Latency and Lytic Reactivation

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