UntRIG(er)ing lncRNAs

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UntRIG(er)ing lncRNAs

GARCIN, Dominique

GARCIN, Dominique. UntRIG(er)ing lncRNAs. Molecular Cell , 2018, vol. 71, no. 1, p. 6-7

PMID : 29979969

DOI : 10.1016/j.molcel.2018.06.026

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Molecular Cell


UntRIG(er)ing lncRNAs

Dominique Garcin1,*

1Department of Microbiology and Molecular Medicine, Centre Me´dical Universitaire, 1 rue Michel Servet, 1211, Geneva 4, Switzerland

*Correspondence:dominique.garcin@unige.ch https://doi.org/10.1016/j.molcel.2018.06.026

In a recent



Jiang et al. (2018)

have shown that lnc-Lsm3b, a long non-coding RNA induced by type I IFN late in the infection in mouse macrophages, prevents further activation of RIG-I acting as a decoy for RIG-I.

RIG-I is a cytoplasmic sentinel that pri- marily detects viral RNA molecular signa- tures. These molecular signatures consist of short dsRNA with a blunt-50ppp-end.

These structures are also very similar to those present in self-RNAs. Hence, the innate immune system must use an extremely specific detection mechanism to trigger a tightly controlled innate and in- flammatory response. An inappropriate or uncontrolled innate response has the po- tential to induce deleterious inflammatory autoimmune diseases (Cao, 2016). To perform its function, RIG-I must continu- ously scan its environment by sampling dsRNA structures in the cytoplasm. Until recently, it was thought that RIG-I binding dsRNA resulted in one of two outcomes depending on the nature of the dsRNA encountered, either: (i) RIG-I is activated, which entails ATP binding, release of the auto-inhibited CARD domains, formation of a tetrameric complex of RIG-I, interac- tion with the CARD domain of the mito- chondrial protein MAVS, and subsequent downstream signaling (Figure 1, left panel) (Kowalinski et al., 2011) or (ii) RIG-I is recycled on the dsRNA, which is coupled to ATP hydrolysis and the ATPase activity of RIG-I (Anchisi et al., 2015a). Thus, RIG-I’s ATPase activity contributes to the discrimination between self and non-self RNAs. This discrimina- tion is rendered complicated by structural similarities between self and non-self as well as by strategies that viruses have evolved to escape detection. In addition, cells have developed strategies to pro- duce self-generated RNAs that can serve as ligands to these cytoplasmic host sen- tinels bypassing viral escape strategies (reviewed inL€assig and Hopfner, 2017).

Recently added to this list is a new class of RNA, the circular RNAs (circRNAs) of both viral and cellular origins that result

from back-splicing. These circRNAs have a regulatory role in gene expression but also have the ability to bind proteins and function as decoys. Only circRNAs of viral origin have the ability to bind and activate RIG-I, whereas those of cellular origin are protected by cellular proteins preventing their binding to RIG-I (Chen et al., 2017).

In a recent issue of Cell, Jiang et al.

have provided evidence that another cellular RNA, a long non-coding RNA (lncRNA), has the ability to bind RIG-I in mouse macrophages. However, in this case, the interaction did not lead to the activation or recycling of RIG-I but rather to a stable ‘‘sterilizing’’ binding (Jiang et al., 2018).

Over the past few years, the role of lncRNAs has become increasingly impor- tant in regulatory processes involving pro- teins binding these RNAs. Jiang et al.

(2018) identified a type I IFN-induced lncRNA, lnc-Lsm3b, that has the ability to bind to RIG-I. In the absence of this lncRNA, late in infection, there is an in- crease in cytokine synthesis and this cor- relates with an increased antiviral state.

Competition experiments show that lnc- Lsm3b competes with bona fide RIG-I ligands for binding to the CTD of RIG-I, the domain that binds RNA to initiate conformational changes required for RIG-I activation. In this case, binding of lnc-Lsm3b to RIG-I does not induce these conformational changes, hence no acti- vation (Figure 1, right panel). The RNA motif that binds RIG-I is a small bulge within a dsRNA structure, and this motif is repeated several times on lnc-Lsm3b.

There is a perfect correlation between the presence and number of these motifs and the ability of lnc-Lsm3b to negatively regulate RIG-I activation. Inter- estingly, lnc-Lsm3b inhibits RIG-I activa-

tion through another mechanism beyond binding the ligand site. One hallmark of RIG-I activation is the formation of a tetra- meric RIG-I complex required for down- stream signaling (Figure 1, left side) (re- viewed in Wu and Hur, 2015). By sequestering multiple RIG-Is as mono- mers without inducing the release of their CARD domains, lnc-Lsm3b not only com- petes with bona fide viral dsRNA RIG-I li- gands, but it also prevents oligomeriza- tion and activation of RIG-I. Consistent with a stable binding of lnc-Lsm3b to RIG-I, RIG-I ATPase activity involved in the recycling of RIG-I from dsRNA is significantly reducedin vitroin the pres- ence of lnc-Lsm3b. RIG-I bound as monomers to lnc-Lsm3b remains in its inactive auto-repressed conformation with the CARD domains bound to the heli- case domain, thus preventing its activa- tion and downstream signaling (Figure 1, right panel).

Interestingly, this is not the first time that such a decoy strategy has been shown to be evoked to limit RIG-I activa- tion. Some arenavirus RNA genomes retain a single unpaired (overhanging) nucleotide when the complementary genome ends anneal to form a dsRNA panhandle structure. Not only does such a structure escape RIG-I activation but it can also acts as a RIG-I decoy (Marq et al., 2011). This strategy may not be a

‘‘viral invention’’ but may simply repro- duce a cellular strategy used to regulate RIG-I activation.

It seems clear that RIG-I has the ability to recognize dsRNA structures well beyond bona fide dsRNA ligands of viral origin. This is exploited by the cell to generate endogenous dsRNAs that in- crease the register of RIG-I activators beyond viral dsRNAs and anti-innate immunity viral strategies (L€assig and 6 Molecular Cell71, July 5, 2018ª2018 Elsevier Inc.


Hopfner, 2017). The motifs recognized by RIG-I in some ‘‘self-RNAs’’ remain largely unknown. Here the RNA motif that is recognized by RIG-I partially meets what is expected from a RIG-I ligand—a dsRNA structure—but here has unpaired nucleo- tides reminiscent of the mismatches found in some viral panhandle structures that prevent RIG-I activation (Anchisi et al., 2015b). Beyond the discrimination between self and non-self, which proves to be more and more complex, it now

appears that RIG-I agonist and antagonist molecules are used to regulate innate im- mune responses. The question then arises whether the same mechanism is used in human cells.

Another question also emerges from this work. The innate immune response results in the production of type I IFN.

This IFN functions to ‘‘prime’’ uninfected cells. This ‘‘priming’’ induces an antiviral state, but also, by stimulating the expres- sion of cellular sentinels, increases the

sensitivity and the extent of the innate response. According to the proposed model (Jiang et al., 2018), the innate im- mune response to viral infection should be impaired in primed uninfected mouse macrophages, which may be dangerous and counterproductive. Is there a regula- tion operating here to restore the ability of these primed uninfected cells to initiate an innate immune response?


Anchisi, S., Guerra, J., and Garcin, D. (2015a).

RIG-I ATPase activity and discrimination of self- RNA versus non-self-RNA. MBio6, e02349.

Anchisi, S., Guerra, J., Mottet-Osman, G., and Gar- cin, D. (2015b). Mismatches in the Influenza A Virus RNA Panhandle Prevent Retinoic Acid-Inducible Gene I (RIG-I) Sensing by Impairing RNA/RIG-I Complex Formation. J. Virol.90, 586–590.

Cao, X. (2016). Self-regulation and cross-regula- tion of pattern-recognition receptor signalling in health and disease. Nat. Rev. Immunol.16, 35–50.

Chen, Y.G., Kim, M.V., Chen, X., Batista, P.J., Aoyama, S., Wilusz, J.E., Iwasaki, A., and Chang, H.Y. (2017). Sensing Self and Foreign Circular RNAs by Intron Identity. Mol. Cell 67, 228–

238.e5, e225.

Jiang, M., Zhang, S., Yang, Z., Lin, H., Zhu, J., Liu, L., Wang, W., Liu, S., Liu, W., Ma, Y., et al. (2018).

Self-Recognition of an Inducible Host lncRNA by RIG-I Feedback Restricts Innate Immune Response. Cell173, 906–919.e13, e913.

Kowalinski, E., Lunardi, T., McCarthy, A.A., Louber, J., Brunel, J., Grigorov, B., Gerlier, D., and Cusack, S. (2011). Structural basis for the acti- vation of innate immune pattern-recognition re- ceptor RIG-I by viral RNA. Cell147, 423–435.

L€assig, C., and Hopfner, K.P. (2017). Discrimina- tion of cytosolic self and non-self RNA by RIG-I- like receptors. J. Biol. Chem.292, 9000–9009.

Marq, J.B., Hausmann, S., Veillard, N., Kolakofsky, D., and Garcin, D. (2011). Short double-stranded RNAs with an overhanging 50ppp-nucleotide, as found in arenavirus genomes, act as RIG-I decoys.

J. Biol. Chem.286, 6108–6116.

Wu, B., and Hur, S. (2015). How RIG-I like recep- tors activate MAVS. Curr. Opin. Virol.12, 91–98.

Figure 1. Model for Negative Regulation of RIG-I Activation by lnc-Lsmb3 RNA

Early in infection (left panel), following RIG-I binding to its substrates, viral 50ppp-dsRNA and ATP, CARDs are released, and tetrameric RIG-I complex is formed, which can interact with the CARD domain of the mitochondrial protein MAVS. This interaction promotes MAVS filament formation required for downstream signaling and activation of type I IFN and cytokine production.

Late in infection (right panel), the increase of RIG-I expression induced by type I IFN should amplify the level of RIG-I activation with the concomitant risk of an exaggerated inflammatory response. lnc-Lsm3b, whose expression is also induced by type I IFN, competes with viral dsRNAs for RIG-I binding resulting in the sequestration of RIG-I in an inactive complex and thus preventing further sustained RIG-I activation and downstream signaling.

Molecular Cell


Molecular Cell71, July 5, 2018 7



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