Dual role of the chromatin-binding factor PHF13 in the pre- and post-integration phases of HIV-1 replication

Abstract

Viruses interact with multiple host cell factors. Some of these are required to promote viral propagation, others have roles in inhibiting infection. Here, we delineate the function of the cellular factor PHF13 (or SPOC1), a putative HIV-1 restriction factor. Early in the HIV-1 replication cycle PHF13 increased the number of integrated proviral copies and the number of infected cells. However, after HIV-1 integration, high levels of PHF13 suppressed viral gene expression. The antiviral activity of PHF13 is counteracted by the viral accessory protein Vpr, which mediates PHF13 degradation. Altogether, the transcriptional master regulator and chromatin binding protein PHF13 does not have purely repressive effects on HIV-1 replication, but also promotes viral integration. By the functional characterization of the dual role of PHF13 during the HIV-1 replication cycle, we reveal a surprising and intricate mechanism through which HIV-1 might regulate the switch from integration to viral gene expression. Furthermore, we identify PHF13 as a cellular target specifically degraded by HIV-1 Vpr.

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

“…Another group found that GSK3β (but not GSK3α) inhibition reduced both replication and viral particle production of HCV but not hepatitis E virus in Huh7.5 cells [175]. Moreover, GSK3-mediated phosphorylation appears to be involved in the destabilization of PHD finger protein 13, a host factor that (amongst other functions) is involved in repressing HIV-1 [176] and human cytomegalovirus gene expression [177]. Direct GSK3α/β-dependent phosphorylation of the coronavirus (CoV) nucelocapsid (N) has been described to be of importance for viral expansion, since GSK3 inhibition reduces both CoV-N phosphorylation and CoV replication [178].…”

Tuning the Orchestra: HCMV vs. Innate Immunity

“…SPOC1 is also a DNA repair factor as it accumulates at DNA double-strand breaks and regulates the DNA damage response (Mund et al, 2012). A restriction activity of SPOC1 has been observed against human adenovirus type 5 (HAdV5) (Schreiner et al, 2013) and HIV-1 (Hofmann et al, 2017). In these specific contexts, SPOC1 inhibits viral replication, but it is also degraded by viral proteins as a negative feedback mechanism.…”

“…Intriguingly, HCMV but not HIV-1 and AdV5 infection promotes and early transient upregulation of SPOC1 through an IE1-mediated mechanisms independent of protein stabilization. At later steps of infection, SPOC1 levels start to decline upon phosphorylation by the serine-threonine kinase glycogen synthase kinase 3β (GSK-3β) (Hofmann et al, 2017). However, contrary to HIV-1 infection, where Vpr has already been identified as the viral protein involved in SPOC1 degradation (Reichel et al, 2018), the mechanism of HCMV-mediated downregulation of SPOC1 still remains obscure.…”

Chromatin-Remodeling Factor SPOC1 Acts as a Cellular Restriction Factor against Human Cytomegalovirus by Repressing the Major Immediate Early Promoter

“…Furthermore, they showed that the HAdV E3 ubiquitin ligase complex E1B-55K/E4-orf6 efficiently antagonizes SPOC1 by inducing its proteasomal degradation early after infection (25). Interestingly, recent reports suggest that SPOC1 plays a dual role during HIV-1 infection (26). Depending on the time point of HIV-1 replication, high SPOC1 levels either improved HIV-1 integration (SPOC1 expression prior to HIV-1 integration) or suppressed viral gene expression (SPOC1 expression after HIV-1 integration).…”

“…Depending on the time point of HIV-1 replication, high SPOC1 levels either improved HIV-1 integration (SPOC1 expression prior to HIV-1 integration) or suppressed viral gene expression (SPOC1 expression after HIV-1 integration). Furthermore, the authors of that study demonstrated that the viral accessory protein Vpr counteracts SPOC1 by targeted degradation (26).…”