Host protein Ku70 binds and protects HIV-1 integrase from proteasomal degradation and is required for HIV replication.

Authors: Zheng Y, Ao Z, Wang B, Jayappa KD, Yao X.
Publisher/Year: J Biol Chem. 2011 May 20;286(20):17722-35. Epub 2011 Mar 29.
Pub Med ID/Journal ID: PMID:21454661


Abstract HIV-1 integrase (IN) is a key viral enzymatic protein acting in several viral replication steps including integration. IN has been shown to be an unstable protein degraded by the N-end rule pathway through the host ubiquitin-proteasome machinery. However, it is still not fully understood how this viral protein is protected from the host ubiquitin-proteasome system (UPS) within cells during HIV replication. In this present study, we provide evidence that the host protein Ku70 interacts with HIV-1 IN and protects it from the K48-linked polyubiquitination proteasomal pathway. Moreover, Ku70 is able to down-regulate the overall protein polyubiquitination level within the host cells and to specifically deubiquitinate IN through their interaction. Mutagenic studies revealed that the C-terminus of IN (230-288) is required for IN binding to the N-terminal part of Ku70 (Ku701-430), and their interaction is independent of Ku70/80 heterodimerization. Finally, knockdown of Ku70 expression in both virus-producing and target CD4+ T cells significantly disrupted HIV-1 replication and rendered 2-LTR circles and integration undetectable, indicating that Ku70 is required for both the early and the late stages of the HIV-1 life cycle. Interestingly, Ku70 was incorporated into the progeny virus in an IN-dependent way. We proposed that Ku70 may interact with IN during viral assembly and accompany HIV-1 IN upon entry into the new target cells, acting to 1) protect IN from the host defense system and 2) assist IN-integration activity. Overall, this report provides another example of how HIV-1 hijacks