The TRAF6-Akt axis is required for efficient lytic replication of KSHV.

TRAF6 is traditionally recognized as an antiviral ubiquitin E3 ligase that positively regulates the production of type I interferon and inflammatory cytokines. However, our study reveals that TRAF6 also plays a crucial role in the lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV). Mechanistically, during KSHV lytic replication, TRAF6 mediates the K63-linked polyubiquitination and activation of Akt, which is required for the efficient viral replication. Disruption of TRAF6 or Akt expression through CRISPR-mediated knockout, or inhibition of TRAF6 or Akt with small molecule inhibitors, reduces KSHV replication efficiency. Conversely, expression of constitutively active Akt can rescue the impaired replication caused by TRAF6 deficiency. Notably, the TRAF6-Akt axis is also required for the lytic replication of Epstein-Barr virus but not for Human cytomegalovirus. These findings highlight the role of the TRAF6-Akt axis in the life cycle of oncogenic herpesviruses and suggest potential therapeutic targets for related diseases.