A Viral Ubiquitin Ligase Has Substrate Preferential SUMO Targeted Ubiquitin Ligase Activity that Counteracts Intrinsic Antiviral Defence

Boutell, Chris; Cuchet-Lourenço, Delphine; Vanni, Emilia A. H.; Orr, Anne; Glaß, Mandy; McFarlane, Steven; Everett, Roger D.

doi:10.1371/journal.ppat.1002245

Cited by 152 publications

(295 citation statements)

References 73 publications

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“…These unexpected findings therefore point to the existence of a highly integrated regulatory loop wherein the substrates, their modifiers (SUMOs) and the catalyser (PML NBs) are all dramatically upregulated during IFN response, promoting the rapid formation of the active, SUMO-conjugated form. This integrated IFN-driven pathway is targeted by multiple viral or bacterial proteins, which abrogate de novo sumoylation, promote desumoylation, degrade SUMO conjugates or de-organize PML NBs 15,47 .…”

Section: Discussionmentioning

confidence: 99%

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Şahin¹,

Ferhi²,

Carnec³

et al. 2014

Nat Commun

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Small ubiquitin-related modifier (SUMO) protein conjugation onto target proteins regulates multiple cellular functions, including defence against pathogens, stemness and senescence. SUMO1 peptides are limiting in quantity and are thus mainly conjugated to high-affinity targets. Conjugation of SUMO2/3 paralogues is primarily stress inducible and may initiate target degradation. Here we demonstrate that the expression of SUMO1/2/3 is dramatically enhanced by interferons through an miRNA-based mechanism involving the Lin28/let-7 axis, a master regulator of stemness. Normal haematopoietic progenitors indeed display much higher SUMO contents than their differentiated progeny. Critically, SUMOs contribute to the antiviral effects of interferons against HSV1 or HIV. Promyelocytic leukemia (PML) nuclear bodies are interferon-induced domains, which facilitate sumoylation of a subset of targets. Our findings thus identify an integrated interferon-responsive PML/SUMO pathway that impedes viral replication by enhancing SUMO conjugation and possibly also modifying the repertoire of targets. Interferon-enhanced post-translational modifications may be essential for senescence or stem cell self-renewal, and initiate SUMO-dependent proteolysis.

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Section: Discussionmentioning

confidence: 99%

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Şahin¹,

Ferhi²,

Carnec³

et al. 2014

Nat Commun

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“…ICP0 is a major multifunctional protein created immediately after infection. Among its major functions are the recruitment of CLOCK histone deacetylase to the viral transcriptome (40), the dissociation of the CoREST/REST/LSD1 repressor complex from its cognate sites on viral DNA (41,42) and the degradation of PML and SP100 (11,15,43). ΔICP0 mutants replicate in U2OS cells but poorly in numerous cell lines, including human (e.g., HEp-2) and African green monkey kidney (Vero) cells (44)(45)(46).…”

Section: At a Low Ratio Of Virus Per Cell δIcp0 Virus Replicates To mentioning

confidence: 99%

“…ICP0 functions as a ubiquitin ligase that in conjunction with ubiquitin-conjugating enzyme UbcH5a degrades PML and SP100 (11,15,43). A curious property of ICP0 is that the protein made early in infection coincident with the time course of degradation of SP100 and PML has a relatively short half-life, whereas that made at later times after infection is stable (60).…”

Section: The Degradation Of Icp0 Early In Infection Is Unrelated To Imentioning

confidence: 99%

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

Roizman

2017

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear domain 10 (ND10) bodies are small (0.1–1 μM) nuclear structures containing both constant [e.g., promyelocytic leukemia protein (PML), SP100, death domain-associated protein (Daxx)] and variable proteins, depending on the function of the cells or the stress to which they are exposed. In herpes simplex virus (HSV)-infected cells, ND10 bodies assemble at the sites of DNA entering the nucleus after infection. In sequence, the ND10 bodies become viral replication compartments, and ICP0, a viral E3 ligase, degrades both PML and SP100. The amounts of PML and SP100 and the number of ND10 structures increase in cells exposed to IFN-β. Earlier studies have shown that PML has three key functions. Thus, (i) the interaction of PML with viral components facilitates the initiation of replication compartments, (ii) viral replication is significantly less affected by IFN-β in PML−/− cells than in parental PML+/+ cells, and (iii) viral yields are significantly lower in PML−/− cells exposed to low ratios of virus per cell compared with parental PML+/+ cells. This report focuses on the function of SP100. In contrast to PML−/− cells, SP100−/− cells retain the sensitivity of parental SP100+/+ cells to IFN-β and support replication of the ΔICP0 virus. At low multiplicities of infection, wild-type virus yields are higher in SP100−/− cells than in parental HEp-2 cells. In addition, the number of viral replication compartments is significantly higher in SP100−/− cells than in parental SP100+/+ cells or in PML−/− cells.

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“…Boutell explained his group's recent findings that elucidate the process. They showed that the recruitment of ND10 proteins to sites of HSV-1 genomes depended upon the SUMO conjugation pathway, because when the E2 SUMO-conjugating enzyme Ubc9 was depleted from cells, the replication of an ICP0-deleted mutant of HSV-1 was partially rescued [13].…”

Section: Future Microbiology Part Ofmentioning

confidence: 99%

“…They regulate the levels of SUMO-modified substrate proteins by orchestrating their ubiquitination and proteasome-mediated degradation. Boutell and colleagues recognized the presence of multiple SIM-like sequences in ICP0, and on that basis, proceeded to demonstrate that the viral protein represents a viral STUbL [13]. Thus, ICP0 could affect the degradation of SUMOmodified PML isoforms in a RING finger-and proteasome-dependent mechanism.…”

Section: Future Microbiology Part Ofmentioning

confidence: 99%

Innate Barriers to Viral Infection

Damania

Blackbourn

2012

Future Microbiol.

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Innate immunity represents the foremost barrier to viral infection. In order to infect a cell efficiently, viruses need to evade innate immune effectors such as interferons and inflammatory cytokines. Pattern recognition receptors can detect viral components or pathogen-associated molecular patterns. These receptors then elicit innate immune responses that result in the generation of type I interferons and proinflammatory cytokines. Organized by the Society for General Microbiology, one session of this conference focused on the current state-of-the-art knowledge on innate barriers to infection of different RNA and DNA viruses. Experts working on innate immunity in the context of viral infection provided insight into different aspects of innate immune recognition and also discussed areas for future research. Here, we provide an overview of the session on innate barriers to infection.

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A Viral Ubiquitin Ligase Has Substrate Preferential SUMO Targeted Ubiquitin Ligase Activity that Counteracts Intrinsic Antiviral Defence

Cited by 152 publications

References 73 publications

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

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

Innate Barriers to Viral Infection

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