The Human Cytomegalovirus Protein TRS1 Inhibits Autophagy via Its Interaction with Beclin 1

INSERM UMR984, Université Paris Sud, Faculté de Pharmacie, Châtenay-Malabry, France.
Journal of Virology (Impact Factor: 4.44). 12/2011; 86(5):2571-84. DOI: 10.1128/JVI.05746-11
Source: PubMed


Human cytomegalovirus modulates macroautophagy in two opposite directions. First, HCMV stimulates autophagy during the early stages of infection, as evident by an increase in the number of autophagosomes and a rise in the autophagic flux. This stimulation occurs independently of de novo viral protein synthesis since UV-inactivated HCMV recapitulates the stimulatory effect on macroautophagy. At later time points of infection, HCMV blocks autophagy (M. Chaumorcel, S. Souquere, G. Pierron, P. Codogno, and A. Esclatine, Autophagy 4:1-8, 2008) by a mechanism that requires de novo viral protein expression. Exploration of the mechanisms used by HCMV to block autophagy unveiled a robust increase of the cellular form of Bcl-2 expression. Although this protein has an anti-autophagy effect via its interaction with Beclin 1, it is not responsible for the inhibition induced by HCMV, probably because of its phosphorylation by c-Jun N-terminal kinase. Here we showed that the HCMV TRS1 protein blocks autophagosome biogenesis and that a TRS1 deletion mutant is defective in autophagy inhibition. TRS1 has previously been shown to neutralize the PKR antiviral effector molecule. Although phosphorylation of eIF2α by PKR has been described as a stimulatory signal to induce autophagy, the PKR-binding domain of TRS1 is dispensable to its inhibitory effect. Our results show that TRS1 interacts with Beclin 1 to inhibit autophagy. We mapped the interaction with Beclin 1 to the N-terminal region of TRS1, and we demonstrated that the Beclin 1-binding domain of TRS1 is essential to inhibit autophagy.

Download full-text


Available from: Wolfram Brune
  • Source
    • "Beclin 1 is a critical component of PI3KC3 complex that triggers the initiation of autophagy, and its function is suppressed through interaction of Bcl-2 with the BH3 domain of Beclin 1 [34]. The HCMV protein TRS1 and the viral homologues of Bcl-2 of Kaposi's sarcoma herpesvirus (KSHV) and murine gamma herpesvirus 68 (γHV-68) have been also shown to inhibit the formation of autophagosomes through their binding to Beclin 1 [9, 35, 36]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The ability to subvert intracellular antiviral defenses is necessary for virus to survive as its replication occurs only in the host cells. Viruses have to modulate cellular processes and antiviral mechanisms to their own advantage during the entire virus life cycle. Autophagy plays important roles in cell regulation. Its function is not only to catabolize aggregate proteins and damaged organelles for recycling but also to serve as innate immunity to remove intracellular pathogenic elements such as viruses. Nevertheless, some viruses have evolved to negatively regulate autophagy by inhibiting its formation. Even more, some viruses have employed autophagy to benefit their replication. To date, there are more and more growing evidences uncovering the functions of many viral proteins to regulate autophagy through different cellular pathways. In this review, we will discuss the relationship between viruses and autophagy and summarize the current knowledge on the functions of viral proteins contributing to affect autophagy process.
    Full-text · Article · Mar 2014
  • Source
    • "Increasing numbers of studies have shown that autophagy is involved in cancer, muscular discord and neurodegeneration, major histocompatibility complex (MHC) antigen presentation, and innate immunity against certain bacteria and viruses [10-13]. Autophagy can be activated by some bacterial or viral infections [14-17], while it is inhibited by others such as HIV-1 and Human cytomegalovirus [18,19]. Autophagy is regulated by several complex signaling pathways. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Subgroup J avian leukosis virus (ALV-J) infection can induce tumor-related diseases in chickens. Previous studies by our laboratory demonstrated that ALV-J infection of DF-1 cells resulted in altered activity and phosphorylation of AKT. However, little is known about the subsequent activation of host DF-1 cells. Results In the current study, autophagy inhibition was observed for ALV-J infected DF-1 cells. Our data showed that the autophagosome protein, microtubule-associated protein 1 light chain 3-II (LC3-II), was reduced considerably in DF-1 cells infected with active ALV-J, while no change was observed for cells infected with inactivated ALV-J. Autophagy inhibition was also confirmed by fluorescence microscopy and transmission electron microscopy. Interestingly, when autophagy was promoted by rapamycin, the titers of ALV-J replication were decreased, and the replication level of ALV-J was significantly enhanced when atg5 (autophagy-related gene 5) was knocked out. Conclusions These results suggested that ALV-J infection could down-regulate autophagy in DF-1 cells during viral replication. This study is the first to report on the relationship between ALV-J infection and autophagy in DF-1 cells.
    Full-text · Article · Jun 2013 · Virology Journal
  • Source
    • "The ICP34.5 and US11 proteins inhibit the phosphorylation of eIF2a at temporally distinct phases of HSV-1 infection, thereby releasing the block to protein synthesis and subsequently inhibiting the induction of autophagy [70, 71]. Similar to alpha-herpesviruses, beta-herpesviruses like hCMV are extremely efficient in blocking autophagosome formation through the TRS1 viral protein which directly interacts and inhibits Beclin1 [72]. Gamma-herpesviruses seem to employ a different mechanism for the inhibition of autophagy which relies on the acquisition of cellular homologues of Bcl-2 protein including BHRF1 and BALF-1 of EBV, Orf16 of Kaposi's sarcoma-associated herpesvirus (KSHV), and M11 of murine γ-herpesvirus 68 (γ-HV68) [73]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Idiopathic pulmonary fibrosis is the most common and severe form of idiopathic interstitial pneumonias. Despite an exponential increase in our understanding of potentially important mediators and mechanisms, the pathogenesis remains elusive, and little therapeutic progress has been made in the last few years. Mortality in 3-5 years is still 50%. Autophagy, a highly conserved homeostatic mechanism necessary for cell survival, has been recently implicated in the pathogenesis of pulmonary disorders. In this paper we aim to highlight some key issues regarding the process of autophagy and its possible association with the pathogenesis of idiopathic pulmonary fibrosis.
    Full-text · Article · Apr 2013
Show more