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

Abstract

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.

Post-transcriptional regulation of antiviral gene expression by N6-methyladenosine

“…Although studies have documented non-canonical activation or delayed stimulation of subsets of ISGs during viral infection, the molecular pathways that control these subsets of ISGs are not well understood ( Pulit-Penaloza et al, 2012 ; Rose et al, 2010 ). However, transcriptional regulators of subsets of ISGs have been identified ( Froggatt et al, 2019 ; Perwitasari et al, 2011 ; Seifert et al, 2019 ), and the mRNA Cap1 methyltransferase CMTR1 can regulate the expression of certain ISGs ( Williams et al, 2020 ). These studies demonstrate that the complexity of ISG regulation extends beyond transcriptional induction.…”

RNA Binding Proteins as Pioneer Determinants of Infection: Protective, Proviral, or Both?

“…As mentioned, a subset of eukaryotic RNAs lead with the cap 0 structure [113,114]. Strikingly, in one study, all of the detectable cap 0 modifications found in vertebrate mRNA contained m6A as the first transcribed base [113].…”

“…As mentioned, a subset of eukaryotic RNAs lead with the cap 0 structure [113,114]. Strikingly, in one study, all of the detectable cap 0 modifications found in vertebrate mRNA contained m6A as the first transcribed base [113]. A cap 1 moiety with m6A as the first transcribed base is distinct from its internal counterpart and thus has its own designation: 2 -O-dimethyladenosine (m6Am, Figure 4a) [123].…”

“…The expression levels of CMTR1 (which was first characterized as "ISG95") are sensitive to IFN stimulation (Figure 4b) [112,113]. Recently, CMTR1 was found to be required for the enhanced expression of other ISGs [114].…”

Co-expression analysis identifies neuro-inflammation as a driver of sensory neuron aging in Aplysia californica

“…Several innate immune mobilized antiviral zinc finger protein orthologs are represented in this module, including PARP12 , ZC3HAVIL , TUT4 , and three orthologs of ZNFX1 , one of which is the hub transcript [ 249 , 252 , 292 , 293 ]. Other transcripts are orthologs of interferon-stimulated genes (ISG) that stimulate or facilitate the expression of other ISG, including ZNFX1 , MRE11 , DTX3L , CMTR1 , and IRF1 [ 222 , 226 , 229 , 244 , 248 ]. Among these ISG orthologs are viral dsRNA sensors ZNFX1 and DDX58 / RIG1 [ 222 , 285 ].…”