A CRISPR-Cas9 screen Reveals STEEP1 as a Key Host Dependency Factor for Epstein-Barr Virus Latent Membrane Protein 1 Trafficking and Signaling

Epstein-Barr virus (EBV) infects most people worldwide. While infection is often benign, it causes infectious mononucleosis, is associated with a range of lymphomas, nasopharyngeal and gastric carcinoma and is a major trigger for autoimmune disease, including multiple sclerosis. The EBV encoded oncogene LMP1 is a key driver of EBV pathogenesis, and its signaling is necessary for viral immortalization of B lymphocytes into continuously growing lymphoblasts (LCLs). Here, we performed a CRISPR genetic screen to identify host factors that support continuous, ligand-independent signaling by LMP1. This analysis identified an ER-resident protein called STEEP1, previously implicated in support of trafficking of the DNA sensor STING, as a key LMP1 partner.We found that STEEP1 associates with LMP1 and supports LMP1 trafficking out of the endoplasmic reticulum to cellular signaling sites. As STEEP1 knockout impaired LMP1 function and LCL survival, our study identifies the STEEP1/LMP1 complex as a therapeutic target.