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Long noncoding RNA: TRIMming the viral load

Cellular & Molecular Immunology volume 16, pages 843–845 (2019)Cite this article

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The cytosolic sensors RLRs consist of three members, (RIG-I, MDA5, and Laboratory of genetics and physiology 2 (LGP2), which recognize viral RNA. These sensors contain a DExD/H-box RNA helicase domain at the C-terminus with an ATP binding motif. RIG-I and MDA5 additionally possess two caspase activation and recruitment domains (CARDs) at the N-terminus, which are required for homotypic CARD-CARD interactions and downstream signaling. LGP2 lacks the CARD and therefore is considered to acts as a negative regulator of the RLR pathway by sequestering RNA away from RIG-I and MDA5.2 However, in vivo genetic studies revealed that LGP2 potentiates RIG-I and MDA5-mediated responses under physiological conditions.3 RIG-I and MDA5 are specialized to recognize viral RNAs with different molecular weights, and MDA5 preferentially binds to long (>1 kb) dsRNA molecules. In contrast, RIG-I participates in the recognition of short (<300 bp) RNA molecules, 5′ppp dsRNA, 5′pp dsRNA or ssRNA. In the inactive state, RIG-I and MDA5 adopt a closed structure with the CARDs concealed by its C-terminal domain (CTD). The interaction of RNA with CTD activates RIG-I by exposing the CARDs, promoting oligomerization and finally interacting with a mitochondrial membrane-associated CARD containing adapter protein interferon-β promoter stimulator-1 (IPS-1), also known as mitochondrial antiviral signaling protein, virus-induced signaling adapter or CARD adapter inducing interferon-β.4 Activation of IPS-1 leads to the recruitment of signaling proteins such as TRAF2, TRAF6, and TRADD. These changes recruit TRAF3 and TANK to induce the activation of TBK1 and IKKε and finally leads to the production of type I and III interferons and proinflammatory cytokines through the transcription factors IRF3/IRF7 and NF-κB, respectively (Fig. 1a).

The RLR pathway is vital for viral defense, and its dysregulation can cause autoimmune diseases;5 therefore, the RLR signaling pathway is tightly regulated at the posttranslational level. Regulation of the RLR pathway by ubiquitination is pivotal for antiviral responses and immune homeostasis and occurs at various levels, such as sensing, signaling and transcription factor activation. Ubiquitin is a small peptide consisting of 76 amino acids, and multiple ubiquitin molecules can be sequentially added to one of the seven lysine (K) residues of ubiquitin (K6, K11, K27, K29, K33, K48, and K63),6 resulting in a variety of ubiquitin chains that can then be covalently linked to a target protein by E3 ubiquitin ligase. This posttranslational modification called ubiquitination can alter the function or stability of a protein depending on the type of ubiquitination. RIG-I is regulated by a number of E3 ubiquitin ligases, K27 and K48-linked ubiquitination by TRIM407 and K48-linked ubiquitination by RNF122,8 and STUB19 promotes proteasomal degradation, while K63-linked ubiquitination promotes oligomerization and RIG-I stabilization. In addition, multiple ubiquitin chains can be added to different lysine residues of RIG-I, and this multisite RIG-I ubiquitination is essential for its activation and helps in fine-tuning of type-I interferon production during virus infection.10 Binding of RNA ligands by RIG-I CTD exposes its CARDs for K63-linked ubiquitination at distinct sites by TRIM25, TRIM4, MEX3c and Riplet.10,11,12,13,14 Ubiquitination stabilizes RIG-I oligomerization and promotes the interaction with the CARD of IPS-1, resulting in IPS-1 aggregation and dimerization in the mitochondrial membrane, required for downstream signaling.

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Fig. 1

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  1. Laboratory of Immunology and Infectious Disease Biology, Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal By-pass road, Bhauri, Bhopal, Madhya Pradesh, 462066, India

    Akhilesh Kumar & Himanshu Kumar

  2. Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Himanshu Kumar

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Kumar, A., Kumar, H. Long noncoding RNA: TRIMming the viral load. Cell Mol Immunol 16, 843–845 (2019). https://doi.org/10.1038/s41423-019-0290-5

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