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

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.

Keywords: Gemin5; LGP2; Leader protease targets; MDA5; RNA-binding proteins.