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ADAR1: A New Target for Immuno-oncology Therapy
Molecular Cell
Spotlight ADAR1: A New Target for Immuno-oncology Therapy Amruta Bhate,1,2 Tao Sun,1,2 and Jin Billy Li1,* 1Stanford
University Department of Genetics, Stanford, CA 94305, USA authors contributed equally *Correspondence: [email protected] https://doi.org/10.1016/j.molcel.2019.02.021 2These
Three recent studies by Ishizuka et al. (2019), Liu et al. (2019), and Gannon et al. (2018) show that deleting RNA editing enzyme ADAR1 could induce higher cell lethality and render tumor cells more vulnerable to immunotherapy, pinpointing ADAR1 as a new immuno-oncology target. Adenosine-to-Inosine (A-to-I) RNA editing is catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes that bind and edit double-stranded RNA (dsRNA). It is widespread in mammals; millions of A-to-I editing events have been identified in the human transcriptome. The vast majority of editing events happen in inverted repeats that form long dsRNAs, and ADAR1 is the primary enzyme responsible for editing these repeats (Tan et al., 2017). Recent work reveals that ADAR1 editing can efficiently neutralize the immunogenicity of the endogenous dsRNAs, keeping the immune response in check (Liddicoat et al., 2015; Mannion et al., 2014; Pestal et al., 2015). The ‘‘self’’ endogenous dsRNAs, if not edited by ADAR1, are recognized as ‘‘non-self’’ pathogenic dsRNAs by the dsRNA immune sensor MDA5 to trigger an innate immune response. ADAR1 editing-deficient mice are embryonic lethal due to type I interferon (IFN) production as well as elevated expression of IFN-stimulated genes (ISGs). Remarkably, the embryonic lethality can be fully rescued upon removal of MDA5 (Liddicoat et al., 2015). In humans, loss-of-function mutations of ADAR1 and gain-of-function mutations of MDA5 lead to autoimmune diseases (Crow, 2015). Thus, editing of dsRNA by ADAR1 plays an important role in preventing aberrant and chronic innate immune response activation. On the other hand, hyper-editing of RNA by elevated ADAR1 activity has been reported in some cancers, raising the question of whether cancer cells exploit the ADAR1 activity to evade immune detection (Fritzell et al., 2018). Three recently published studies (Gannon et al., 2018; Ishizuka et al.,
2019; Liu et al., 2019) show that certain types of tumor cells have a unique vulnerability to ADAR1 loss and that deleting ADAR1 could sensitize tumors to immunotherapy (Figure 1). All three studies, through independent genetic evidence from various cancer cells, reported that ADAR1 deletion causes reduced cancer cell viability. They all concur that the IFN pathway is crucial for the observed phenotype, as genetic deletion of the key components of the pathway diminished the cell growth inhibition. In a previous study, the Haining group identified ADAR1 as a top candidate to boost cancer immunotherapy in a loss-of-function CRISPR screen of transplantable B16 melanoma tumors in mice treated with anti-PD1 therapy (Manguso et al., 2017). Now, in Ishizuka et al. (2019), the Haining group has further characterized the role of ADAR1 in tumor biology, showing that loss of ADAR1 indeed renders tumor cells sensitive to immunotherapy and overcomes resistance to checkpoint blockade. Additionally, a global reshaping of immune cell profile occurs in the ADAR1-null tumors along with increased levels of IFNs. Furthermore, they have demonstrated that deleting ADAR1 restores sensitivity to immunotherapy even in B2m null tumor cells, which cannot be recognized by CD8+ T cells and are immunotherapy resistant. This finding suggests that sufficient inflammation caused by ADAR1 deletion can overcome resistance to checkpoint blockade caused by loss of tumor-specific CD8+ T cell response. Both Liu et al. (2019) and Gannon et al. (2018), on the other hand, identified ADAR1 by mining existing databases—
866 Molecular Cell 73, March 7, 2019 ª 2019 Elsevier Inc.
such as shRNA screens of tumor suppressors—and validated these results by CRISPR-mediated knockout experiments. Both studies showed that certain types of cancer cell lines have a higher ISG expression and that these cells are more sensitive to ADAR1 deletion. Intriguingly, Liu et al. (2019) showed that certain primary tumors, even without great infiltration from immune cells, have a high level of ISG expression, indicating that tumors per se can be a source of IFN. Given that ADAR1 is the editing enzyme neutralizing immunogenic dsRNAs, all three groups set out to examine which pathway is triggered in the ADAR1 deletion tumors, and all of them identified the PKR pathway. Gannon et al. (2018) individually knocked out specific nucleic acid sensors and found that knockout of PKR, but not MDA5 or STING, can rescue the lethality phenotype of ADAR1-null cells. Both Ishizuka et al. (2019) and Liu et al. (2019) performed an unbiased, CRISPRbased screen of the ADAR1 knockout or knockdown cells and identified PKR as the strongest suppressor of ADAR1 deletion. Although this was not found in the in vitro screen, Ishizuka et al. (2019) showed that MDA5 pathway is also critical for the ADAR1 deletion phenotype in the in vivo model using transplantable B16 melanoma tumors. In the above experiments, ADAR1 / tumors remain sensitive to immunotherapy when either PKR or MDA5 is knocked out individually, but not simultaneously. The two sensors appear to be required for different aspects of immune-mediated tumor suppression, with PKR mediating the IFN-dependent growth arrest while MDA5 is required for
Molecular Cell
Spotlight
Figure 1. Ablation of ADAR1 Sensitizes Tumor Cells to Immune Infiltration and Growth Inhibition In a tumor cell, nucleic acid sensors activated by specific stimuli turn on the expression of interferonstimulated genes (ISGs) and type I IFN production. This leads to higher expression of ADAR1 and increased editing of dsRNAs. Thus, MDA5 and PKR are not activated, as the edited dsRNAs cannot be sensed (left side). Upon ablation of ADAR1, dsRNAs remain unedited and are detected by MDA5 and PKR. Activation of MDA5 boosts type I IFN production, leading to increased inflammation and immune infiltration. PKR activation leads to translation inhibition and growth arrest (right side).
the enhanced inflammation and immune infiltration. These three complementary studies with different focuses and approaches all pointed to ADAR1 as a checkpoint for cancer immunotherapy. Loss of ADAR1 leading to PKR activation and cell lethality under IFN treatment has been known to the field (Chung et al., 2018). What is exciting is that tumor cells per se can produce IFN, which could make such tumors specifically vulnerable to loss of ADAR1 in comparison to normal tissues. Loss of ADAR1 probably leads to accumulation of endogenous immunogenic dsRNAs, which triggers IFN responses via nucleic acid sensors. Intriguingly, the normally deleterious process of turning on nucleic acid sensing pathways might be beneficial in the context of cancer treatment. Recent studies have shown promising results from activating the cCAS-STING cytosolic dsDNA sensing pathway, which is parallel to the MDA5 cytosolic dsRNA sensing pathway, for cancer immunotherapy (Ng et al., 2018). Furthermore, the MDA5 dsRNA sensing pathway can also be turned on by other mechanisms such as the epigenetic-inhibitor-mediated
overexpression of endogenous retrovirus (ERV) genes that form dsRNAs (Jones et al., 2019). All three studies suggest the existence of endogenous immunogenic dsRNAs as another source of immune induction for cancer immunotherapy. The findings from these studies also led to further questions, especially about the dsRNA sensors MDA5 and PKR and the dsDNA sensor STING. The chronic IFN production in some tumors appears to be STING dependent (Liu et al., 2019). It would be interesting to delineate what stimulates STING-dependent IFN production and how this affects the crosstalk between STING and MDA5/ PKR. Mechanistically, ADAR1 is known to edit endogenous dsRNAs to dampen the MDA5 pathway in vivo. Underscoring the importance of MDA5 downstream of ADAR1, the embryonic lethality of the ADAR1-editing-deficient mouse can be fully rescued by deleting MDA5, but not PKR (Liddicoat et al., 2015; Wang et al., 2004). However, all three studies reveal that knockout of PKR, but not MDA5, rescues the growth arrest of ADAR1 / cancer cells. This discrepancy may indicate a complicated syner-
gistic interaction between PKR and MDA5 pathways in actual organisms that is missing in vitro. Indeed, Ishizuka et al. (2019) showed that, although PKR and MDA5 mediate diverse pathways upon ADAR1 ablation, either of them is sufficient to render cancer cells sensitive to immunotherapy using their transplantable B16 tumor model. Future work is needed to examine whether the same effect of ADAR1 inhibition on tumor survival can be recapitulated in animal models and whether this is mediated by PKR and/or MDA5 in vivo. To mechanistically understand how PKR and MDA5 activate dsRNA sensing, there is a compelling need to identify immunogenic dsRNAs that may differ between them. Nevertheless, these three studies, together with previous findings that reveal the in vivo function of ADAR1 to evade the dsRNA sensing pathway, provide strong evidence for ADAR1 as a novel target for immuno-oncology therapy. DECLARATION OF INTERESTS The laboratory of Jin Billy Li receives services in kind from Takeda Pharmaceutical Company. REFERENCES Chung, H., Calis, J.J.A., Wu, X., Sun, T., Yu, Y., Sarbanes, S.L., Dao Thi, V.L., Shilvock, A.R., Hoffmann, H.H., Rosenberg, B.R., et al. (2018). Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown. Cell 172, 811– 824.e814. Crow, Y.J. (2015). Type I interferonopathies: mendelian type I interferon up-regulation. Curr. Opin. Immunol. 32, 7–12. Fritzell, K., Xu, L.D., Lagergren, J., and O¨hman, M. (2018). ADARs and editing: The role of A-to-I RNA modification in cancer progression. Semin. Cell Dev. Biol. 79, 123–130. Gannon, H.S., Zou, T., Kiessling, M.K., Gao, G.F., Cai, D., Choi, P.S., Ivan, A.P., Buchumenski, I., Berger, A.C., Goldstein, J.T., et al. (2018). Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells. Nat. Commun. 9, 5450. Ishizuka, J.J., Manguso, R.T., Cheruiyot, C.K., Bi, K., Panda, A., Iracheta-Vellve, A., Miller, B.C., Du, P.P., Yates, K.B., Dubrot, J., et al. (2019). Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature 565, 43–48. Jones, P.A., Ohtani, H., Chakravarthy, A., and De Carvalho, D.D. (2019). Epigenetic therapy in immune-oncology. Nat. Rev. Cancer. https://doi. org/10.1038/s41568-019-0109-9. Liddicoat, B.J., Piskol, R., Chalk, A.M., Ramaswami, G., Higuchi, M., Hartner, J.C., Li,
Molecular Cell 73, March 7, 2019 867
Molecular Cell
Spotlight J.B., Seeburg, P.H., and Walkley, C.R. (2015). RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115–1120. Liu, H., Golji, J., Brodeur, L.K., Chung, F.S., Chen, J.T., deBeaumont, R.S., Bullock, C.P., Jones, M.D., Kerr, G., Li, L., et al. (2019). Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss. Nat. Med. 25, 95–102. Manguso, R.T., Pope, H.W., Zimmer, M.D., Brown, F.D., Yates, K.B., Miller, B.C., Collins, N.B., Bi, K., LaFleur, M.W., Juneja, V.R., et al. (2017). In vivo CRISPR screening iden-
868 Molecular Cell 73, March 7, 2019
tifies Ptpn2 as a cancer immunotherapy target. Nature 547, 413–418. Mannion, N.M., Greenwood, S.M., Young, R., Cox, S., Brindle, J., Read, D., Nella˚ker, C., Vesely, C., Ponting, C.P., McLaughlin, P.J., et al. (2014). The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep. 9, 1482–1494. Ng, K.W., Marshall, E.A., Bell, J.C., and Lam, W.L. (2018). cGAS-STING and Cancer: Dichotomous Roles in Tumor Immunity and Development. Trends Immunol. 39, 44–54. Pestal, K., Funk, C.C., Snyder, J.M., Price, N.D., Treuting, P.M., and Stetson, D.B. (2015). Isoforms
of RNA-Editing Enzyme ADAR1 Independently Control Nucleic Acid Sensor MDA5-Driven Autoimmunity and Multi-organ Development. Immunity 43, 933–944. Tan, M.H., Li, Q., Shanmugam, R., Piskol, R., Kohler, J., Young, A.N., Liu, K.I., Zhang, R., Ramaswami, G., Ariyoshi, K., et al. (2017). Dynamic landscape and regulation of RNA editing in mammals. Nature 550, 249–254. Wang, Q., Miyakoda, M., Yang, W., Khillan, J., Stachura, D.L., Weiss, M.J., and Nishikura, K. (2004). Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J. Biol. Chem. 279, 4952–4961.
Spotlight ADAR1: A New Target for Immuno-oncology Therapy Amruta Bhate,1,2 Tao Sun,1,2 and Jin Billy Li1,* 1Stanford
University Department of Genetics, Stanford, CA 94305, USA authors contributed equally *Correspondence: [email protected] https://doi.org/10.1016/j.molcel.2019.02.021 2These
Three recent studies by Ishizuka et al. (2019), Liu et al. (2019), and Gannon et al. (2018) show that deleting RNA editing enzyme ADAR1 could induce higher cell lethality and render tumor cells more vulnerable to immunotherapy, pinpointing ADAR1 as a new immuno-oncology target. Adenosine-to-Inosine (A-to-I) RNA editing is catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes that bind and edit double-stranded RNA (dsRNA). It is widespread in mammals; millions of A-to-I editing events have been identified in the human transcriptome. The vast majority of editing events happen in inverted repeats that form long dsRNAs, and ADAR1 is the primary enzyme responsible for editing these repeats (Tan et al., 2017). Recent work reveals that ADAR1 editing can efficiently neutralize the immunogenicity of the endogenous dsRNAs, keeping the immune response in check (Liddicoat et al., 2015; Mannion et al., 2014; Pestal et al., 2015). The ‘‘self’’ endogenous dsRNAs, if not edited by ADAR1, are recognized as ‘‘non-self’’ pathogenic dsRNAs by the dsRNA immune sensor MDA5 to trigger an innate immune response. ADAR1 editing-deficient mice are embryonic lethal due to type I interferon (IFN) production as well as elevated expression of IFN-stimulated genes (ISGs). Remarkably, the embryonic lethality can be fully rescued upon removal of MDA5 (Liddicoat et al., 2015). In humans, loss-of-function mutations of ADAR1 and gain-of-function mutations of MDA5 lead to autoimmune diseases (Crow, 2015). Thus, editing of dsRNA by ADAR1 plays an important role in preventing aberrant and chronic innate immune response activation. On the other hand, hyper-editing of RNA by elevated ADAR1 activity has been reported in some cancers, raising the question of whether cancer cells exploit the ADAR1 activity to evade immune detection (Fritzell et al., 2018). Three recently published studies (Gannon et al., 2018; Ishizuka et al.,
2019; Liu et al., 2019) show that certain types of tumor cells have a unique vulnerability to ADAR1 loss and that deleting ADAR1 could sensitize tumors to immunotherapy (Figure 1). All three studies, through independent genetic evidence from various cancer cells, reported that ADAR1 deletion causes reduced cancer cell viability. They all concur that the IFN pathway is crucial for the observed phenotype, as genetic deletion of the key components of the pathway diminished the cell growth inhibition. In a previous study, the Haining group identified ADAR1 as a top candidate to boost cancer immunotherapy in a loss-of-function CRISPR screen of transplantable B16 melanoma tumors in mice treated with anti-PD1 therapy (Manguso et al., 2017). Now, in Ishizuka et al. (2019), the Haining group has further characterized the role of ADAR1 in tumor biology, showing that loss of ADAR1 indeed renders tumor cells sensitive to immunotherapy and overcomes resistance to checkpoint blockade. Additionally, a global reshaping of immune cell profile occurs in the ADAR1-null tumors along with increased levels of IFNs. Furthermore, they have demonstrated that deleting ADAR1 restores sensitivity to immunotherapy even in B2m null tumor cells, which cannot be recognized by CD8+ T cells and are immunotherapy resistant. This finding suggests that sufficient inflammation caused by ADAR1 deletion can overcome resistance to checkpoint blockade caused by loss of tumor-specific CD8+ T cell response. Both Liu et al. (2019) and Gannon et al. (2018), on the other hand, identified ADAR1 by mining existing databases—
866 Molecular Cell 73, March 7, 2019 ª 2019 Elsevier Inc.
such as shRNA screens of tumor suppressors—and validated these results by CRISPR-mediated knockout experiments. Both studies showed that certain types of cancer cell lines have a higher ISG expression and that these cells are more sensitive to ADAR1 deletion. Intriguingly, Liu et al. (2019) showed that certain primary tumors, even without great infiltration from immune cells, have a high level of ISG expression, indicating that tumors per se can be a source of IFN. Given that ADAR1 is the editing enzyme neutralizing immunogenic dsRNAs, all three groups set out to examine which pathway is triggered in the ADAR1 deletion tumors, and all of them identified the PKR pathway. Gannon et al. (2018) individually knocked out specific nucleic acid sensors and found that knockout of PKR, but not MDA5 or STING, can rescue the lethality phenotype of ADAR1-null cells. Both Ishizuka et al. (2019) and Liu et al. (2019) performed an unbiased, CRISPRbased screen of the ADAR1 knockout or knockdown cells and identified PKR as the strongest suppressor of ADAR1 deletion. Although this was not found in the in vitro screen, Ishizuka et al. (2019) showed that MDA5 pathway is also critical for the ADAR1 deletion phenotype in the in vivo model using transplantable B16 melanoma tumors. In the above experiments, ADAR1 / tumors remain sensitive to immunotherapy when either PKR or MDA5 is knocked out individually, but not simultaneously. The two sensors appear to be required for different aspects of immune-mediated tumor suppression, with PKR mediating the IFN-dependent growth arrest while MDA5 is required for
Molecular Cell
Spotlight
Figure 1. Ablation of ADAR1 Sensitizes Tumor Cells to Immune Infiltration and Growth Inhibition In a tumor cell, nucleic acid sensors activated by specific stimuli turn on the expression of interferonstimulated genes (ISGs) and type I IFN production. This leads to higher expression of ADAR1 and increased editing of dsRNAs. Thus, MDA5 and PKR are not activated, as the edited dsRNAs cannot be sensed (left side). Upon ablation of ADAR1, dsRNAs remain unedited and are detected by MDA5 and PKR. Activation of MDA5 boosts type I IFN production, leading to increased inflammation and immune infiltration. PKR activation leads to translation inhibition and growth arrest (right side).
the enhanced inflammation and immune infiltration. These three complementary studies with different focuses and approaches all pointed to ADAR1 as a checkpoint for cancer immunotherapy. Loss of ADAR1 leading to PKR activation and cell lethality under IFN treatment has been known to the field (Chung et al., 2018). What is exciting is that tumor cells per se can produce IFN, which could make such tumors specifically vulnerable to loss of ADAR1 in comparison to normal tissues. Loss of ADAR1 probably leads to accumulation of endogenous immunogenic dsRNAs, which triggers IFN responses via nucleic acid sensors. Intriguingly, the normally deleterious process of turning on nucleic acid sensing pathways might be beneficial in the context of cancer treatment. Recent studies have shown promising results from activating the cCAS-STING cytosolic dsDNA sensing pathway, which is parallel to the MDA5 cytosolic dsRNA sensing pathway, for cancer immunotherapy (Ng et al., 2018). Furthermore, the MDA5 dsRNA sensing pathway can also be turned on by other mechanisms such as the epigenetic-inhibitor-mediated
overexpression of endogenous retrovirus (ERV) genes that form dsRNAs (Jones et al., 2019). All three studies suggest the existence of endogenous immunogenic dsRNAs as another source of immune induction for cancer immunotherapy. The findings from these studies also led to further questions, especially about the dsRNA sensors MDA5 and PKR and the dsDNA sensor STING. The chronic IFN production in some tumors appears to be STING dependent (Liu et al., 2019). It would be interesting to delineate what stimulates STING-dependent IFN production and how this affects the crosstalk between STING and MDA5/ PKR. Mechanistically, ADAR1 is known to edit endogenous dsRNAs to dampen the MDA5 pathway in vivo. Underscoring the importance of MDA5 downstream of ADAR1, the embryonic lethality of the ADAR1-editing-deficient mouse can be fully rescued by deleting MDA5, but not PKR (Liddicoat et al., 2015; Wang et al., 2004). However, all three studies reveal that knockout of PKR, but not MDA5, rescues the growth arrest of ADAR1 / cancer cells. This discrepancy may indicate a complicated syner-
gistic interaction between PKR and MDA5 pathways in actual organisms that is missing in vitro. Indeed, Ishizuka et al. (2019) showed that, although PKR and MDA5 mediate diverse pathways upon ADAR1 ablation, either of them is sufficient to render cancer cells sensitive to immunotherapy using their transplantable B16 tumor model. Future work is needed to examine whether the same effect of ADAR1 inhibition on tumor survival can be recapitulated in animal models and whether this is mediated by PKR and/or MDA5 in vivo. To mechanistically understand how PKR and MDA5 activate dsRNA sensing, there is a compelling need to identify immunogenic dsRNAs that may differ between them. Nevertheless, these three studies, together with previous findings that reveal the in vivo function of ADAR1 to evade the dsRNA sensing pathway, provide strong evidence for ADAR1 as a novel target for immuno-oncology therapy. DECLARATION OF INTERESTS The laboratory of Jin Billy Li receives services in kind from Takeda Pharmaceutical Company. REFERENCES Chung, H., Calis, J.J.A., Wu, X., Sun, T., Yu, Y., Sarbanes, S.L., Dao Thi, V.L., Shilvock, A.R., Hoffmann, H.H., Rosenberg, B.R., et al. (2018). Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown. Cell 172, 811– 824.e814. Crow, Y.J. (2015). Type I interferonopathies: mendelian type I interferon up-regulation. Curr. Opin. Immunol. 32, 7–12. Fritzell, K., Xu, L.D., Lagergren, J., and O¨hman, M. (2018). ADARs and editing: The role of A-to-I RNA modification in cancer progression. Semin. Cell Dev. Biol. 79, 123–130. Gannon, H.S., Zou, T., Kiessling, M.K., Gao, G.F., Cai, D., Choi, P.S., Ivan, A.P., Buchumenski, I., Berger, A.C., Goldstein, J.T., et al. (2018). Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells. Nat. Commun. 9, 5450. Ishizuka, J.J., Manguso, R.T., Cheruiyot, C.K., Bi, K., Panda, A., Iracheta-Vellve, A., Miller, B.C., Du, P.P., Yates, K.B., Dubrot, J., et al. (2019). Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature 565, 43–48. Jones, P.A., Ohtani, H., Chakravarthy, A., and De Carvalho, D.D. (2019). Epigenetic therapy in immune-oncology. Nat. Rev. Cancer. https://doi. org/10.1038/s41568-019-0109-9. Liddicoat, B.J., Piskol, R., Chalk, A.M., Ramaswami, G., Higuchi, M., Hartner, J.C., Li,
Molecular Cell 73, March 7, 2019 867
Molecular Cell
Spotlight J.B., Seeburg, P.H., and Walkley, C.R. (2015). RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115–1120. Liu, H., Golji, J., Brodeur, L.K., Chung, F.S., Chen, J.T., deBeaumont, R.S., Bullock, C.P., Jones, M.D., Kerr, G., Li, L., et al. (2019). Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss. Nat. Med. 25, 95–102. Manguso, R.T., Pope, H.W., Zimmer, M.D., Brown, F.D., Yates, K.B., Miller, B.C., Collins, N.B., Bi, K., LaFleur, M.W., Juneja, V.R., et al. (2017). In vivo CRISPR screening iden-
868 Molecular Cell 73, March 7, 2019
tifies Ptpn2 as a cancer immunotherapy target. Nature 547, 413–418. Mannion, N.M., Greenwood, S.M., Young, R., Cox, S., Brindle, J., Read, D., Nella˚ker, C., Vesely, C., Ponting, C.P., McLaughlin, P.J., et al. (2014). The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep. 9, 1482–1494. Ng, K.W., Marshall, E.A., Bell, J.C., and Lam, W.L. (2018). cGAS-STING and Cancer: Dichotomous Roles in Tumor Immunity and Development. Trends Immunol. 39, 44–54. Pestal, K., Funk, C.C., Snyder, J.M., Price, N.D., Treuting, P.M., and Stetson, D.B. (2015). Isoforms
of RNA-Editing Enzyme ADAR1 Independently Control Nucleic Acid Sensor MDA5-Driven Autoimmunity and Multi-organ Development. Immunity 43, 933–944. Tan, M.H., Li, Q., Shanmugam, R., Piskol, R., Kohler, J., Young, A.N., Liu, K.I., Zhang, R., Ramaswami, G., Ariyoshi, K., et al. (2017). Dynamic landscape and regulation of RNA editing in mammals. Nature 550, 249–254. Wang, Q., Miyakoda, M., Yang, W., Khillan, J., Stachura, D.L., Weiss, M.J., and Nishikura, K. (2004). Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J. Biol. Chem. 279, 4952–4961.