NRZ complex facilitates virus infection via enhancing ER–LD contacts

Lipid droplets (LDs), originating from the ER, play critical roles in lipid metabolism. ER–LD contacts enable lipid exchange and support essential cellular processes. However, how viruses utilize ER–LD coordination remains elusive. Here, we demonstrate that hepatitis C virus (HCV) infection markedly increases LDs abundance and enhances ER–LD contacts. Through a targeted screen of ER–LD tethering proteins, we identified that the NRZ complex, composed of nonsteroidal anti-inflammatory drug-activated gene (NAG), RAD50 interactor 1 (RINT1) and zeste white 10 (ZW10), is essential for HCV-induced ER–LD association and viral infection. Mechanistically, RINT1 and ZW10 interact with the HCV envelope protein E1. Ectopic E1 expression is sufficient to promote ER–LD contacts, which are abolished upon NRZ depletion. NRZ depletion also impairs Dengue virus (DENV) and Zika virus (ZIKV) infection, suggesting its conserved proviral function. Together, this work uncovers a critical mechanism by which host inter-organelle tethering complexes regulate viral infection, offering new insights into virus–host interactions and potential antiviral targets.