The small GTPase RAB1B promotes antiviral innate immunity by interacting with TNF receptor–associated factor 3 (TRAF3)

Beachboard, Dia C.; Park, Moonhee; Vijayan, Madhuvanthi; Snider, Daltry L.; Fernando, Dillon J.; Williams, Graham D.; Stanley, Sydney; McFadden, Michael J.; Horner, Stacy M.

doi:10.1074/jbc.ra119.007917

Cited by 23 publications

(19 citation statements)

References 55 publications

(56 reference statements)

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“…All cell lines were grown at 37°C with supplementation with 5% CO 2 . 293T and Vero (CCL-3216 and CCL-81) cells were obtained from ATCC; Huh7 cells were a gift of Michael Gale, Jr. (University of Washington); Huh7-STAT1 KO (Huh7-STAT1 knockout) cells have been described previously (49). To generate short hairpin RNA (shRNA) IFIT1 cells, 293T cells were cotransfected with psPax2 and pMD2.G (Addgene plasmids; catalog no.…”

Section: Methodsmentioning

confidence: 99%

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: Methodsmentioning

confidence: 99%

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

Williams

Gokhale

Snider

et al. 2020

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“…All cell lines were grown at 37°C supplemented with 5% CO 2 . 293T and Vero (CCL-3216 and CCL-81) cells were obtained from ATCC; Huh7 cells were a gift of Dr. Michael Gale Jr. at the University of Washington; Huh7-STAT1 KO have been described previously (49). Generation of shRNA IFIT1 cells: 293T cells were co-transfected with psPax2 and pMD2.G (Addgene plasmids #12260 and #12259), as well as pLKO.1 (50) containing either non-targeting or IFIT1 shRNA (Sigma, TRC1, Clone: TRCN0000158439).…”

Section: Methodsmentioning

confidence: 99%

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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“…I propose that interferon signalling induces PI4KB delocalization from the Golgi to the ER, like occurs following nutrient depletion for both PI4KB and PIK1/FRQ1 together with the reverse shuttling of the PI(4)P phosphatase suppressor of actin 1 (SAC1) from the ER to the Golgi [57,73]. Indeed, interferon signalling and energy deprivation share the characteristic of triggering autophagy [74,75], and several interferon-inducible Golgi GTPases drive the movement of Golgi membranes, with proteins such as APOL2, to MERCs [76][77][78]. Such inflammation-induced delocalization of PI4KB-APOL3 complexes from the Golgi to MERCs could participate in the initiation of autophagy [56] and eventually phagophore elongation from mitochondrial membranes [59].…”

Section: Relevance Of the Model To Kidney Diseasementioning

confidence: 99%

The function of apolipoproteins L (APOLs): relevance for kidney disease, neurotransmission disorders, cancer and viral infection

Pays

2020

The FEBS Journal

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The discovery that apolipoprotein L1 (APOL1) is the trypanolytic factor of human serum raised interest about the function of APOLs, especially following the unexpected finding that in addition to their protective action against sleeping sickness, APOL1 C-terminal variants also cause kidney disease. Based on the analysis of the structure and trypanolytic activity of APOL1, it was proposed that APOLs could function as ion channels of intracellular membranes and be involved in mechanisms triggering programmed cell death. In this review, the recent finding that APOL1 and APOL3 inversely control the synthesis of phosphatidylinositol-4-phosphate (PI(4)P) by the Golgi PI(4)-kinase IIIB (PI4KB) is commented. APOL3 promotes Ca 2+-dependent activation of PI4KB, but due to their increased interaction with APOL3, APOL1 C-terminal variants can inactivate APOL3, leading to reduction of Golgi PI(4)P synthesis. The impact of APOLs on several pathological processes that depend on Golgi PI(4)P levels is discussed. I propose that through their effect on PI4KB activity, APOLs control not only actomyosin activities related to vesicular trafficking, but also the generation and elongation of autophagosomes induced by inflammation.

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The small GTPase RAB1B promotes antiviral innate immunity by interacting with TNF receptor–associated factor 3 (TRAF3)

Cited by 23 publications

References 55 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

The function of apolipoproteins L (APOLs): relevance for kidney disease, neurotransmission disorders, cancer and viral infection

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