The following is a summary of the “Effect of variants in LGP2 on MDA5-mediated activation of interferon response and suppression of hepatitis D virus replication,” published in the January 2023 issue of Hepatology by Gillich, et al.

To activate the antiviral interferon (IFN) response, RIG-I, MDA5, and LGP2 are examples of RIG-I-like receptors (RLRs) that sense viral RNA. Despite its inability to initiate the IFN response directly, LGP2 does so by influencing RIG-I and MDA5 signalling. In addition, MDA5 is able to detect HDV, a small RNA virus responsible for the most severe form of viral hepatitis. However, the precise method by which IFNs are induced and how they inhibit HDV replication remains unknown. Thus, they set out to elucidate LGP2 and its clinically relevant variations’ roles in these procedures.

Both the HDV-susceptible HepaRGNTCP cells and primary human hepatocytes lacked a sufficient number of RLRs. Multiple LGP2 variant expression was achieved through cell reconstitution. Time-resolved measurements of HDV and IFN markers were taken. Pull-down tests examined the interactions between LGP2, MDA5, and RNA. The MDA5-mediated IFN response triggered by HDV infection requires LGP2. LGP2’s RNA-binding and ATPase functions are necessary for this induction. While the IFN response only modestly inhibited HDV replication in quiescent cells, it significantly attenuated HDV spread via cell division. LGP2 Q425R is more common in Africans who develop mild chronic hepatitis D, and it mediates a larger baseline IFN response, a faster HDV-induced IFN response, and stronger HDV suppression. 

Mechanistically, stable MDA5-RNA complex formation required RNA binding by LGP2. The Q425R LGP2 mutation improved MDA5’s binding to RNA. LGP2 stabilizes the MDA5-RNA binding necessary for subsequent HDV-induced antiviral IFN response signaling. The gain-of-function variation Q425R LGP2 found in nature may play a role in a milder form of hepatitis D.

Source: sciencedirect.com/science/article/pii/S0168827822031130