Upregulation of ATF4-LAMP3 Axis by ORF45 Facilitates Lytic Replication of Kaposi’s Sarcoma-Associated Herpesvirus

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a g-oncogenic herpesvirus, and both lytic and latent infections play important roles in its pathogenesis and tumorigenic properties. Multiple cellular pathways and diverse mediators are hijacked by viral proteins and are used to support KSHV lytic replication. In previous studies, we revealed that KSHV ORF45 promoted KSHV transcription and translation by inducing sustained p90 ribosomal S6 kinase (RSK) activation and the phosphorylation of its substrates c-Fos and eIF4B. However, the cellular mediators required for lytic replication remain largely unknown. Here, we reveal that ORF45 activates eIF2a phosphorylation and ATF4 translation and then upregulates the expression of lysosome-associated membrane protein 3 (LAMP3) in an ATF4-dependent manner during KSHV lytic replication. Consequently, LAMP3 promotes Akt and ERK activation and then facilitates lytic gene expression and virion production. Furthermore, ATF4 enhances lytic replication through LAMP3, and LAMP3 acts in an ATF4-independent manner. Our findings suggest that the ATF4-LAMP3 axis is upregulated by ORF45 through ER stress activation during the KSHV lytic life cycle and, in turn, facilitates optimal lytic replication.