Innate immune sensor LGP2 is cleaved by the Leader protease of foot-and-mouth disease virus

• Published in: PLoS pathogens 2018-06, Vol.14 (6), p.e1007135
• Main Authors: Rodríguez Pulido, Miguel, Sánchez-Aparicio, María Teresa, Martínez-Salas, Encarnación, García-Sastre, Adolfo, Sobrino, Francisco, Sáiz, Margarita
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Antiviral activity; Antiviral agents; Biology and Life Sciences; Cells, Cultured; Chlorocebus aethiops; Cleavage; Conserved sequence; Cricetinae; Cytoplasm; Diagnosis; DNA helicase; Endopeptidases - genetics; Endopeptidases - metabolism; Foot & mouth disease; Foot and mouth disease; Foot-and-Mouth Disease - immunology; Foot-and-Mouth Disease - pathology; Foot-and-Mouth Disease - virology; Foot-and-Mouth Disease Virus - enzymology; Foot-and-Mouth Disease Virus - immunology; Genetics; Genomes; Health aspects; HEK293 Cells; Humans; Immune Evasion - immunology; Immune response; Immunity, Innate - immunology; Infections; Innate immunity; Kinases; Medicine; Medicine and Health Sciences; Melanoma; mRNA; Pathogenesis; Pattern recognition receptors; Protease; Proteinase; Proteins; Proteolysis; Receptors; Research and Analysis Methods; Retinoic acid; Ribonucleic acid; RNA; RNA helicase; RNA Helicases - genetics; RNA Helicases - immunology; RNA Helicases - metabolism; RNA viruses; Vero Cells; Viral infections; Viruses; β-Interferon
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007135

The RNA helicase LGP2 (Laboratory of Genetics and Physiology 2) is a non-signaling member of the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), whose pivotal role on innate immune responses against RNA viruses is being increasingly uncovered. LGP2 is known to work in synergy with melanoma differentiation-associated gene 5 (MDA5) to promote the antiviral response induced by picornavirus infection. Here, we describe the activity of the foot-and-mouth disease virus (FMDV) Leader protease (Lpro) targeting LGP2 for cleavage. When LGP2 and Lpro were co-expressed, cleavage products were observed in an Lpro dose-dependent manner while co-expression with a catalytically inactive Lpro mutant had no effect on LGP2 levels or pattern. We further show that Lpro localizes and immunoprecipitates with LGP2 in transfected cells supporting their interaction within the cytoplasm. Evidence of LGP2 proteolysis was also detected during FMDV infection. Moreover, the inhibitory effect of LGP2 overexpression on FMDV growth observed was reverted when Lpro was co-expressed, concomitant with lower levels of IFN-β mRNA and antiviral activity in those cells. The Lpro target site in LGP2 was identified as an RGRAR sequence in a conserved helicase motif whose replacement to EGEAE abrogated LGP2 cleavage by Lpro. Taken together, these data suggest that LGP2 cleavage by the Leader protease of aphthoviruses may represent a novel antagonistic mechanism for immune evasion.