EMG1 methyltransferase activity affects ribosome occupancy at KSHV uORFs

Viruses lack their own translational machinery and rely exclusively on the host cell for synthesis of viral proteins. Viruses have evolved diverse mechanisms to redirect the host cell translation apparatus to favor viral transcripts. A unique mechanism employed by Kaposi's sarcoma-associated herpesvirus (KSHV) involves manipulation of cellular ribosome composition, producing virus-induced specialized ribosomes. These ribosomes scan through KSHV upstream open reading frames (uORFs) in late lytic genes, allowing efficient translation of downstream main KSHV ORFs. Here, we highlight the enhanced association of the ribosomal biogenesis factor EMG1 with precursor-40S ribosome complexes during KSHV lytic replication. Depletion of EMG1 results in significantly reduced expression of viral proteins and progression through the lytic cascade, culminating in a dramatic reduction of infectious virus production. We further demonstrate that the methyltransferase activity of EMG1 is required for effective regulation of translation of KSHV uORFs in late lytic genes.