A non-canonical JAK/STAT pathway promotes viral replication through the lipoprotein receptor-related protein in ticks.

Ticks transmit numerous viruses that pose significant threats to human and animal health, however, the molecular interactions between ticks and viruses remain poorly understood. Using Langat virus (LGTV)-a surrogate for tick-borne encephalitis virus (TBEV), we show that the JAK/STAT pathway promotes viral infection in Haemaphysalis longicornis. Rather than directly interacting with viral proteins, this proviral effect is mediated by a low-density lipoprotein receptor-related protein (LRP), whose expression is regulated by STAT. Silencing LRP in H. longicornis reduced LGTV infection, while ectopic expression of LRP enhanced it. Unlike its mammalian counterparts, H. longicornis LRP lacks a transmembrane domain and localizes intracellularly. Functionally, LRP promotes lipophagy, leading to lipid droplets breakdown and providing energy to support viral replication. Together, these findings reveal a non-canonical mechanism by which the JAK/STAT pathway facilitates LGTV replication through STAT-dependent regulation of an atypical, intracellular LRP that drives lipophagy.