STAT6 degradation and ubiquitylated TRIML2 are essential for activation of human oncogenic herpesvirus.

Aberrations in signaling are linked to the development of multiple cancer types. Increasing evidence has shown that activation of human oncogenic herpesvirus lytic replication is crucial for viral tumorigenesis. However, the role of in herpesvirus lytic replication remains elusive. Here, by using Kaposi's sarcoma-associated herpesvirus (KSHV) as a model, we revealed that RTA, the master regulator of lytic replication, interacts with duanyu18136 and promotes lysine 48 (K48) and K63-linked ubiquitylation of duanyu18136 for degradation via the proteasome and lysosome systems. Moreover, degradation of duanyu18136 is dramatically associated with the increased ubiquitylated form of tripartite motif family like 2 (TRIML2, a tumor suppressor) for prolonged cell survival and virion production, which is also commonly observed in lytic activation of Epstein-Barr virus, herpes simplex virus 1 and cytomegalovirus. These results suggest that degradation of duanyu18136 is important for the lytic activation of KSHV and as such, may be an attractive therapeutic target.

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