Retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2) are RIG-I-like receptors (RLRs), which detect viral RNA to activate the antiviral interferon (IFN) response. LGP2 modifies RIG-I and MDA5 signaling since it is unable to initiate the IFN response on its own. MDA5 detects HDV, a tiny RNA virus that causes the most severe kind of viral hepatitis. Uncertainty surrounds the mechanism behind IFN induction and its impact on HDV replication. For a study, researchers sought to clarify how LGP2 and its therapeutically useful variations function in these processes.

In HDV-sensitive HepaRGNTPC cells and primary human hepatocytes, RLRs were decreased. To express several LGP2 variants, cells were reconstituted. The levels of HDV and IFN markers were measured over time. By using pull-down assays, interaction investigations between LGP2, MDA5, and RNA were conducted.

The MDA5-mediated IFN response brought on by HDV infection depended on LGP2. LGP2 must engage in both RNA binding and ATPase activity for induction. The IFN response significantly lowered cell division-mediated HDV spread but only slightly decreased HDV replication in dormant cells. In Africans with less severe chronic hepatitis D, an LGP2 variant (Q425R) predominates, which mediated a detectably larger basal and quicker HDV-induced IFN response as well as a stronger HDV suppression. In terms of mechanics, stable MDA5-RNA complex formation required LGP2 RNA binding. The Q425R LGP2 mutation improved MDA5 binding to RNA.

LGP2 stabilized the MDA5-RNA association needed for downstream signaling and was crucial for mounting an antiviral IFN response triggered by HDV. In addition, the naturally occurring gain-of-function variation of LGP2, known as Q425R, may be a factor in the shortened course of hepatitis D.

Reference: journal-of-hepatology.eu/article/S0168-8278(22)03113-0/fulltext