Ruelas Debbie S, Chan Jonathan K, Oh Eugene, Heidersbach Amy J, Hebbeler Andrew M, Chavez Leonard, Verdin Eric, Rape Michael, Greene Warner C
From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158, the Biomedical Sciences Program and.
From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158.
J Biol Chem. 2015 May 29;290(22):13736-48. doi: 10.1074/jbc.M115.641837. Epub 2015 Apr 14.
The presence of a small number of infected but transcriptionally dormant cells currently thwarts a cure for the more than 35 million individuals infected with HIV. Reactivation of these latently infected cells may result in three fates: 1) cell death due to a viral cytopathic effect, 2) cell death due to immune clearance, or 3) a retreat into latency. Uncovering the dynamics of HIV gene expression and silencing in the latent reservoir will be crucial for developing an HIV-1 cure. Here we identify and characterize an intracellular circuit involving TRIM32, an HIV activator, and miR-155, a microRNA that may promote a return to latency in these transiently activated reservoir cells. Notably, we demonstrate that TRIM32, an E3 ubiquitin ligase, promotes reactivation from latency by directly modifying IκBα, leading to a novel mechanism of NF-κB induction not involving IκB kinase activation.
目前，少数受感染但转录处于休眠状态的细胞阻碍了治愈超过3500万艾滋病毒感染者的进程。这些潜伏感染细胞的重新激活可能导致三种结果：1）由于病毒细胞病变效应导致细胞死亡；2）由于免疫清除导致细胞死亡；3）重新进入潜伏状态。揭示潜伏库中HIV基因表达和沉默的动态变化对于开发治愈HIV-1的方法至关重要。在这里，我们鉴定并表征了一个细胞内回路，该回路涉及TRIM32（一种HIV激活剂）和miR-155（一种可能促进这些瞬时激活的库细胞恢复潜伏状态的 microRNA）。值得注意的是，我们证明E3泛素连接酶TRIM32通过直接修饰IκBα促进从潜伏状态重新激活，从而导致一种不涉及IκB激酶激活的NF-κB诱导新机制。
