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Summary: Our knowledge of the regulatory mechanisms that govern the replication of the rubella virus (RV) in human cells is limited. To gain insight into the host-pathogen interaction, we conducted a loss-of-function screening using the CRISPR-Cas9 system in the human placenta-derived JAR cells. We identified sphingomyelin synthase 1 (SGMS1 or SMS1) as a susceptibility factor for RV infection. Genetic knockout of SGMS1 rendered JAR cells resistant to infection by RV. The re-introduction of SGMS1 restored cellular susceptibility to RV infection. The restricted step of RV infection was post-endocytosis processes associated with the endosomal acidification. In the late phase of the RV replication cycle, the maintenance of viral persistence was disrupted, partly due to the attenuated viral gene expression. Our results shed light on the unique regulation of RV replication by a host factor during the early and late phases of viral life cycle.