PML/TRIM19-Dependent Inhibition of Retroviral Reverse-Transcription by Daxx

Abstract

PML (Promyelocytic Leukemia protein), also known as TRIM19, belongs to the family of tripartite motif (TRIM) proteins. PML is mainly expressed in the nucleus, where it forms dynamic structures known as PML nuclear bodies that recruit many other proteins, such as Sp100 and Daxx. While the role of PML/TRIM19 in antiviral defense is well documented, its effect on HIV-1 infection remains unclear. Here we show that infection by HIV-1 and other retroviruses triggers the formation of PML cytoplasmic bodies, as early as 30 minutes post-infection. Quantification of the number and size of PML cytoplasmic bodies revealed that they last approximately 8 h, with a peak at 2 h post-infection. PML re-localization is blocked by reverse-transcription inhibitors and is not observed following infection with unrelated viruses, suggesting it is specifically triggered by retroviral reverse-transcription. Furthermore, we show that PML interferes with an early step of retroviral infection since PML knockdown dramatically increases reverse-transcription efficiency. We demonstrate that PML does not inhibit directly retroviral infection but acts through the stabilization of one of its well-characterized partners, Daxx. In the presence of PML, cytoplasmic Daxx is found in the vicinity of incoming HIV-1 capsids and inhibits reverse-transcription. Interestingly, Daxx not only interferes with exogenous retroviral infections but can also inhibit retrotransposition of endogenous retroviruses, thus identifying Daxx as a broad cellular inhibitor of reverse-transcription. Altogether, these findings unravel a novel antiviral function for PML and PML nuclear body-associated protein Daxx.

Emerging Role of PML Nuclear Bodies in Innate Immune Signaling

“…While in vivo experiments with PML knockout mice demonstrated restriction of the arenavirus lymphocytic choriomeningitis virus (LCMV) and the rhabdovirus vesicular stomatitis virus (VSV) more than a decade ago, convincing data for an involvement of PML in HIV-1 restriction were only recently provided by two publications (4,5). They report that PML-NBs undergo a rapid relocalization into cytoplasmic bodies after infection with HIV-1 and other retroviruses, thus enabling an interference with early viral events in the cytoplasm.…”

“…The observation that PML-NBs are targeted and modified by many viruses during infection set off a longstanding debate as to whether PML-NBs exert a pro-or antiviral function and led to a fruitful area of virology research over the past 20 years. Interestingly, these studies revealed that viruses, even representatives of the same virus family, trigger diverse modifications of PML-NBs during infection, ranging from proteasomal degradation of NB components by herpes simplex virus type 1 (HSV-1), to dispersal of PML-NBs by human cytomegalovirus (HCMV), to a rearrangement of PML-NB foci into nuclear track-like structures by adenoviruses or a relocalization of PML into cytoplasmic bodies by HIV-1 (3)(4)(5). While there are a few examples of viral factors that undergo interactions with PML-NBs in order to exploit these structures for the benefit of the virus, the main body of evidence supports a role of PML-NBs as components of the antiviral defense against a variety of DNA and RNA viruses (reviewed in reference 3).…”

Precision autophagy directed by receptor regulators – emerging examples within the TRIM family

“…3A); the known examples include TRIM5 (O'Connor et al, 2010), TRIM50 , TRIM55 (Lange et al, 2005;Pizon et al, 2013;Mandell et al, 2014), TRIM13 (Tomar et al, 2012), TRIM17 and TRIM49 (Mandell et al, 2014), TRIM21 , as well as TRIM76 (Blandin et al, 2013). Furthermore, p62 can colocalize with TRIM63 in the cytoplasm and with TRIM19 in the nucleus within the nuclear PML bodies (Pankiv et al, 2010), although this might not be restricted to the nucleus because TRIM19 functions in the cytoplasm as well (Lin et al, 2004;Dutrieux et al, 2015). The association with p62 might link TRIMs indirectly to LC3B (as discussed above); this is of significance for those TRIMs with no evidence of direct binding to LC3B.…”

The SP100 component of ND10 enhances accumulation of PML and suppresses replication and the assembly of HSV replication compartments

“…A central and as-yet unresolved question is whether PML or SP100 plays a role in the early transcription of viral genes after infection (14,42,(47)(48)(49)(50)(51). Both PML and SP100 are degraded within the first 6 hpi, and thus the major effect of PML or SP100 on the transcription of viral DNA would occur during that period (11).…”