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Uncovering targets of the Leader protease: Linking RNA‐mediated pathways and antiviral defense

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Abstract RNA viruses have developed specialized mechanisms to subvert host RNA‐binding proteins (RBPs) favoring their own gene expression. The Leader (L) protein of foot‐and‐mouth disease virus, a member of the Picornaviridae family, is a papain‐like cysteine protease that self‐cleaves from the polyprotein. Early in infection, the L protease cleaves the translation initiation factors eIF4GI and eIF4GII, inducing the shutdown of cap‐dependent translation. However, the cleavage sites on the viral polyprotein, eIF4GI, and eIF4GII differ in sequence, challenging the definition of a consensus site for L targets. Identification of Gemin5 and Daxx proteolytic products in infected cells unveiled a motif centered on the RKAR sequence. The RBP Gemin5 is a member of the survival of motor neurons complex, a ribosome interacting protein, and a translation downregulator. Likewise, the Fas‐ligand Daxx is a multifunctional adaptor that plays key roles in transcription control, apoptosis, and innate immune antiviral response. Remarkably, the cleavage site on the RNA helicases MDA5 and LGP2, two relevant immune sensors of the retinoic acid‐inducible gene‐I (RIG‐I)‐like receptors family, resembles the L target site of Gemin5 and Daxx, and similar cleavage sites have been reported in ISG15 and TBK1, two proteins involved in type I interferon response and signaling pathway, respectively. In this review we dissect the features of the L cleavage sites in essential RBPs, eventually helping in the discovery of novel L targets. This article is categorized under: RNA in Disease and Development > RNA in Disease Translation > Translation Regulation
Overview of RNA‐binding proteins modifications operating in cells during RNA viral infections. Major alterations affecting RNA‐dependent pathways in cells infected with RNA viruses are indicated
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Outline of Gemin5 functional domains. (a) Diagram of the Lpro cleavage sites in Gemin5 protein. The structural domains of Gemin5 (170 kDa) are represented at the top. The WD repeats located at the N‐terminus are involved in snRNPs assembly and ribosome interaction. The TPR‐like domain in the central region mediates dimerization of the protein. The non‐canonical RNA binding site (RBS1) located at the C‐terminus harbors an IDR, and contributes to selective translation control counteracting the negative effect of Gemin5 in global translation. In contrast, the unstable RBS2/p21 moiety downregulates IRES‐dependent translation. The products p85 and p57 resulting from the sequential Lpro cleavage at the RKAR and TKRL sites are depicted. the role of the protein fragments in translation upregulation or downregulation, and RNA‐binding capacity is indicated. (b) Structural features of the RKAR motif. Residues are colored according to the conservation, from magenta (identity) to cyan (variable). The scissors mark the Lpro cleavage motif. The helix 1 is depicted above the sequence. Residues buried up to 40%, 80%, or 100% in the dimerization interface are denoted with a white, gray or black dot. The approximate position of the RKAR motif on the three‐dimensional structure of the TPR‐like dimer is depicted by a double arrow
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Amino acid sequences of the L protease target sites. (a) Diagram of the FMDV viral genome. For simplicity, only the IRES element and a truncated form of the open reading frame are depicted. Arrows indicate the initiation sites of the Lab and Lb proteins. The amino acid sequence cleaved by Lpro at the L‐P1 junction is indicated. Red letters denote basic residues on the cleavage site, while green letters depict the GAGQS sequence conserved among FMDV isolates. Numbers indicate the position of residues upstream (1–7) and downstream (1′–5′) of the scissile bond. (b) Amino acid sequence of eIF4GI and eIF4GII cleavage sites. (c) Sequence of the identified cleavage sites in Gemin5, Daxx, LGP2, MDA5, ISG15, and TBK1 proteins. Red letters depict the position of basic residues; the shaded box highlights the similarity of the type of amino acid between Gemin5‐1 and FMDV L‐P1
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Translation > Translation Regulation
RNA in Disease and Development > RNA in Disease

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