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Lncrna Malat1 Inhibition of TDP43 Cleavage Suppresses IRF3-Initiated Antiviral Innate Immunity

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Lncrna Malat1 Inhibition of TDP43 Cleavage Suppresses IRF3-Initiated Antiviral Innate Immunity LncRNA Malat1 inhibition of TDP43 cleavage suppresses IRF3-initiated antiviral innate immunity Wei Liua, Ziqiao Wanga, Lun Liua, Zongheng Yanga, Shuo Liua, Zhongfei Maa, Yin Liua, Yuanwu Mab, Lianfeng Zhangb, Xuan Zhangc, Minghong Jianga,1, and Xuetao Caoa,d,e,1 aDepartment of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, 100005 Beijing, China; bInstitute of Laboratory Animal Science, Chinese Academy of Medical Sciences, 100021 Beijing, China; cDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 100730 Beijing, China; dNational Key Laboratory of Medical Immunology and Institute of Immunology, Navy Medical University, 200433 Shanghai, China; and eCollege of Life Science, Nankai University, 300071 Tianjin, China Edited by Akinori Takaoka, Hokkaido University, Sapporo, Japan, and accepted by Editorial Board Member Tadatsugu Taniguchi August 3, 2020 (receivedfor review March 1, 2020) Long noncoding RNAs (lncRNAs) involved in the regulation of degradation of host mRNAs (8–11). Many viruses induce wide- antiviral innate immune responses need to be further identified. spread host RNA decay through virally encoded endonucleases to By functionally screening the lncRNAs in macrophages, here we reduce activation of immune response and provide access to the identified lncRNA Malat1, abundant in the nucleus but signifi- host’s resources for viral replication. It is estimated that up to two- cantly down-regulated after viral infection, as a negative regulator thirds of total mRNAs are degraded upon expression by these of antiviral type I IFN (IFN-I) production. Malat1 directly bound to viral endonucleases (12). A significant fraction of lncRNAs are the transactive response DNA-binding protein (TDP43) in the nu- located in the nucleus and nuclear lncRNAs play important roles cleus and prevented activation of TDP43 by blocking the activated in physiological, biological, and pathological processes via differ- caspase-3-mediated TDP43 cleavage to TDP35. The cleaved TDP35 ent mechanisms (13, 14). However, the role of nuclear abundant increased the nuclear IRF3 protein level by binding and degrading lncRNAs in regulating RNA metabolism and RBP activity in the Rbck1 pre-mRNA to prevent IRF3 proteasomal degradation upon antiviral innate immune response remains to be further investigated. viral infection, thus selectively promoting antiviral IFN-I production. In this study, we functionally screen the differently expressed Deficiency of Malat1 enhanced antiviral innate responses in vivo, lncRNAs in macrophages and identify the nuclear abundant IMMUNOLOGY AND INFLAMMATION accompanying the increased IFN-I production and reduced viral bur- lncRNA Malat1 as a negative regulator of antiviral type I IFN den. Importantly, the reduced MALAT1, augmented IRF3, and in- IFNA production. We find that Malat1 can bind TDP43, inhibit the creased mRNA were found in peripheral blood mononuclear cleavage of TDP43 to its active form TDP35, then reduce nuclear cells (PBMCs) from systemic lupus erythematosus (SLE) patients. IRF3 level in resting cells, maintaining immune homeostasis. Therefore, the down-regulation of MALAT1 in virus-infected cells Upon viral infection, Malat1 expression is down-regulated and or in human cells from autoimmune diseases will increase host resis- releases TDP43 for its activation via cleavage to its active form tance against viral infection or lead to autoinflammatory interferono- pathies via the increased type I IFN production. Our results demonstrate TDP35, then TDP35 prevents IRF3 proteasomal degradation and that the nuclear Malat1 suppresses antiviral innate responses by thus promotes IRF3-initiated antiviral type I IFNs production, targeting TDP43 activation via RNA-RBP interactive network, adding in- feedback benefitting the host against viral infection. Interestingly, sight to the molecular regulation of innate responses and autoimmune pathogenesis. Significance long noncoding RNA | Malat1 | TDP43 | type I interferon | innate immunity LncRNAs have been identified as regulating antiviral innate responses via different targets through various ways. Whether s the first line of defense against viral infection, the pro- there is an abundant and highly conserved lncRNA in the nu- Aduction of type I interferons (IFN-I) (IFN-α and IFN-β), cleus which may regulate antiviral innate signaling through a plays a central role by activating the expression of hundreds of new mechanism remains to be investigated. Here, we identify Malat1 IFN-stimulated genes (ISGs) for establishing an “antiviral state” that viral infection-reduced expression of feedback to restrict viral replication within infected cells (1). Insufficient promotes IRF3-initiated type I IFN production in the innate re- Malat1 production of IFNs causes chronic viral infections, while exces- sponse against viral infection. binds to TDP43 and sive amounts of IFNs are also harmful to the host, inducing prevents its cleavage mediated by activated caspase-3. The autoimmune inflammation and type I interferonopathies (2–4). cleaved TDP35 inhibits IRF3 degradation through promoting Therefore, it is of vital importance to precisely regulate the the degradation of pre-mRNA of Rbck1, an E3 ubiquitin ligase MALAT1 production of IFNs both in temporal and spatial dimensions to targeting IRF3. Aberrant reduction and IRF3 activation ensure the induction of potent antiviral innate response against are found in SLE patients, providing one mechanistic explanation viral infection but also avoid the occurrence of autoimmune for why SLE patients always have type I interferonopathies. diseases. The transcription factor IFN regulatory factor 3 (IRF3) Author contributions: M.J. and X.C. designed research; W.L., Z.W., L.L., Z.Y., S.L., Z.M., Y.L., is critical for IFNs production and directs expression of diverse Y.M., L.Z., and X.Z. performed research; M.J. and X.C. analyzed data; M.J. and X.C. wrote genes in the antiviral immune response (5). Activation of IRF3 the paper; and X.Z. provided the clinical samples. involves virus infection-induced phosphorylation at several sites The authors declare no competing interest. in the C terminal, IRF3 dimerization, and translocation to the This article is a PNAS Direct Submission. A.T. is a guest editor invited by the nucleus. However, how the IRF3 activity for initiating innate gene Editorial Board. expression is tightly regulated remains to be fully understood. Published under the PNAS license. Long noncoding RNAs (lncRNAs) are involved in many biolog- 1To whom correspondence may be addressed. Email: [email protected] or caoxt@ ical processes, including immunity and inflammation (6, 7). They immunol.org. participate in the battle between host and virus via different mech- This article contains supporting information online at https://www.pnas.org/lookup/suppl/ anisms, including regulating the activity of RNA-binding proteins doi:10.1073/pnas.2003932117/-/DCSupplemental. (RBPs) as well as RNA metabolism, especially the translation and www.pnas.org/cgi/doi/10.1073/pnas.2003932117 PNAS Latest Articles | 1of12 Downloaded by guest on September 29, 2021 the reduced MALAT1 and increased IRF3 in peripheral blood transcript 1 (Malat1) robustly decreased virus replication in mac- mononuclear cells (PBMCs) from systemic lupus erythematosus rophages upon GFP-VSV infection for 12 h (SI Appendix, Fig. (SLE) patients with type I interferonopathies were confirmed. S1C). Notably, Malat1 was the fourth most abundant lncRNA in Thus, our findings provide a potential target for controlling viral the uninfected cells and its expression was significantly reduced infection and IFN-I-related inflammatory autoimmune diseases. upon VSV infection (Fig. 1A). Malat1 was universally and highly expressed in immune organs and immune cells including macro- Results phages (SI Appendix,Fig.S1D and E), suggesting that Malat1 The Expression of Nuclear lncRNA Malat1 Decreases upon Viral Infection. might be involved in the regulation of antiviral innate immune Through RNA sequencing (RNA-Seq), we analyzed nuclear response. lncRNA profiling in RAW264.7 cells with or without vesicular Northern blot and fluorescence in situ hybridization (FISH) stomatitis virus (VSV) infection after isolation of nuclear RNAs assay further showed that the expression of Malat1 significantly (SI Appendix,Fig.S1A). The differentially expressed lncRNAs decreased in macrophages upon VSV infection (Fig. 1 B and C). (more than twofold change) are ranked according to their expres- Fluorescence probes to Malat1 exhibited punctuate staining only sion abundance in cells without VSV infection (Fig. 1A). We iso- in the nuclear compartment of cells (Fig. 1C). In addition, in- lated primary peritoneal macrophages from 8-wk-old C57BL/6 male fections with encephalomyocarditis virus (EMCV) (recognized mice and transfected the mixture composition of small interfering by melanoma differentiation-associated protein 5 [MDA5]) and RNAs (siRNAs) and antisense oligonucleotide (ASO) targeting the DNA virus herpes simplex virus type 1 (HSV-1) could also re- top 20 candidate RNAs, respectively (SI Appendix,Fig.S1B). Then duce Malat1 expression (Fig. 1D). In contrast, Toll-like receptor we detected the intracellular GFP intensity with high-content (TLR) ligands, such as lipopolysaccharide (LPS) and poly (I:C), screening (HCS) in cells upon GFP-VSV infection. We found could not
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