Emerging Role of PML Nuclear Bodies in Innate Immune Signaling

Abstract

Research in the last 2 decades has demonstrated that a specific organelle of the cell nucleus, termed PML nuclear body (PML-NB) or nuclear domain 10 (ND10), is frequently modified during viral infection. This correlates with antagonization of a direct repressive function of individual PML-NB components, such as the PML, hDaxx, Sp100, or ATRX protein, that are able to act as cellular restriction factors. Recent studies now reveal an emerging role of PML-NBs as coregulatory structures of both type I and type II interferon responses. This emphasizes that targeting of PML-NBs by viral regulatory proteins has evolved as a strategy to compromise intrinsic antiviral defense and innate immune responses. P romyelocytic leukemia (PML) protein, a member of the tripartite motif (TRIM) protein family, is the key component of subnuclear structures known as PML nuclear bodies (PML-NBs) or nuclear domains 10 (ND10). PML-NBs are dynamic foci that consist of numerous permanently or transiently associated proteins and, consequently, have been implicated in the regulation of diverse cellular functions, including the cell cycle, apoptosis, senescence, stress, and DNA damage responses (reviewed in reference 1). Although the underlying biochemical function of these subnuclear structures is still unclear, three models can be found in the literature, proposing PML-NBs to be nuclear protein depots, sites of nuclear activities (e.g., transcription), or hotspots for posttranslational modifications. In particular, since nearly all PMLassociated proteins are modified by SUMO and SUMOylation of PML is essential for the integrity of PML-NBs, these structures may form "catalytic surfaces" for SUMOylation (1). This is of importance since recent studies suggest that the SUMO pathway is required for the regulation of innate immune signaling and intrinsic immunity during viral infection (reviewed in reference 2). 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 (3-5). 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). PML-NBs AND INTRINSIC IMMUNITYThe role of PML-NBs in intrinsic immunity, which represents the first line of intracellular defense agains...

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

“…Previous studies have shown that PML is a potent effector of IFN in that it is induced by IFN and that the suppression of viral replication in PML −/− cells is significantly reduced compared with that observed in parental PML +/+ cells (5,31,32,61). Because SP100 is independently induced by IFN, the question arose concerning its role as an effector of IFN.…”

“…They consist of an outer shell composed of PML, a set of constant proteins (e.g., CBP, Daxx, SP100 nuclear antigen), and various other proteins depending on the particular stress or function of the ND10 bodies (1)(2)(3)(4)(5)(6)(7). ND10 bodies have drawn attention recently, in large part because of increasing evidence suggesting that they sense and respond to infection (5,8). For example, ND10 bodies have been shown to assemble de novo at herpes simplex virus 1 (HSV-1) DNA newly released from capsids at nuclear pores (9,10).…”

The Role of Nuclear Antiviral Factors against Invading DNA Viruses: The Immediate Fate of Incoming Viral Genomes

“…The first interpretation would assume that host cells have the potential to respond to different viruses using a common mechanism, but each virus has specific countermeasures that prevent genome targeting by nuclear antiviral factors to different degrees, explaining apparent differences in the cellular response. This view has been propagated to some extent in the literature [5,6,25]. An alternative interpretation is that the observed differences in a set of viral systems indeed reflect distinct cellular responses (or absence thereof) against each virus.…”

“…Importantly, some (but not all) of the observations appear similar among different DNA viruses, leading to a generalized concept in which viral DNA genomes are immediately targeted by a set of nuclear antiviral factors in a common way [5,6,25]. By carefully reading the literature, however, we reach the conclusion that for many DNA viruses, the interplay between nuclear antiviral factors and incoming viral genomes immediately following genome import remains to be shown.…”

“…Nevertheless, these studies clearly elucidate a model in which incoming HSV-1 genomes activate an unknown antiviral mechanism(s) that induces relocalization of PML-NB components onto viral genomes in a SUMO-SIM-dependent manner, while ICP0 antagonizes this cellular response, in part, by disrupting the bodies. This idea, consolidated through HSV-1 studies, is the basis of the current model for the nuclear antiviral response against incoming viral genomes [5,6,25]. …”