LXR-inducible host E3 ligase IDOL targets a human cytomegalovirus reactivation determinant to promote latency

Abstract

SummaryLiver X receptor (LXR) signaling broadly restricts virus replication; however, the mechanisms of restriction are poorly defined. Here, we demonstrate that the LXR-inducible cellular E3 ligase IDOL (inducible degrader of low-density lipoprotein receptor, LDLR) restricts replication of the beta-herpesvirus, human cytomegalovirus (HCMV), for the establishment of viral latency. IDOL is highly expressed in undifferentiated hematopoietic cells where HCMV establishes latency, but is sharply downregulated upon differentiation, a stimulus for reactivation. Importantly, IDOL restricts replication by driving the instability of a key viral determinant required for reactivation, the 33-kDa protein encoded byUL136(UL136p33).UL136encodes multiple proteins that differentially impact latency and reactivation. UL136p33 is targeted for rapid turnover by the proteasome and its stabilization by mutation of lysine residues to arginine results in a failure to quiet replication for latency. We show that IDOL interacts with and targets UL136p33 for turnover, but not the stabilized variant. While induction of IDOL prevents reactivation from latency, IDOL depletion increases viral gene expression in undifferentiated hematopoietic cells. This work establishes the UL136p33-IDOL interaction as a key regulator of the bistable switch between latency and reactivation. It further suggests a model whereby a key viral determinant of HCMV reactivation is regulated by a host E3 ligase and acts as a sensor at the tipping point between the decision to maintain the latent state or exit latency for reactivation.SignificanceHerpesviruses establish life-long latent infections, which pose an important risk for disease particularly in the immunocompromised. Our work is focused on the beta-herpesvirus, human cytomegalovirus (HCMV) that latently infects the majority of the population worldwide. Defining the mechanisms by which HCMV establish latency or reactivate from latency is important to controlling disease. Here, we demonstrate that the cellular inducible degrader of low-density lipoprotein receptor, IDOL, targets a HCMV determinant of reactivation for degradation. The instability of this determinant is important for the establishment of latency. This work defines a pivotal virus-host interaction that allows HCMV to sense changes in host biology to navigate decisions to establish latency or replicate.