The Disruption of ND10 during Herpes Simplex Virus Infection Correlates with the Vmw110- and Proteasome-Dependent Loss of Several PML Isoforms

ABSTRACT The small nuclear structures known as ND10 or PML nuclear bodies have been implicated in a variety of cellular processes including response to stress and interferons, oncogenesis, and viral infection, but little is known about their biochemical properties. Recently, a ubiquitin-specific protease enzyme (named HAUSP) and a ubiquitin-homology family protein (PIC1) have been found associated with ND10. HAUSP binds strongly to Vmw110, a herpesvirus regulatory protein which has the ability to disrupt ND10, while PIC1 was identified as a protein which interacts with PML, the prototype ND10 protein. We have investigated the role of ubiquitin-related pathways in the mechanism of ND10 disruption by Vmw110 and the effect of virus infection on PML stability. The results show that the disruption of ND10 during virus infection correlates with the loss of several PML isoforms and this process is dependent on active proteasomes. The PML isoforms that are most sensitive to virus infection correspond closely to those which have recently been identified as being covalently conjugated to PIC1. In addition, a large number of PIC1-protein conjugates can be detected following transfection of a PIC1 expression plasmid, and many of these are also eliminated in a Vmw110-dependent manner during virus infection. These observations provide a biochemical mechanism to explain the observed effects of Vmw110 on ND10 and suggest a simple yet powerful mechanism by which Vmw110 might function during virus infection.

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[64]  M. Dasso,et al.  Ubc9p and the conjugation of SUMO-1 to RanGAP1 and RanBP2 , 1998, Current Biology.

[65]  A. Dejean,et al.  Conjugation with the ubiquitin‐related modifier SUMO‐1 regulates the partitioning of PML within the nucleus , 1998, The EMBO journal.

[66]  T. Sternsdorf,et al.  Evidence for Covalent Modification of the Nuclear Dot–associated Proteins PML and Sp100 by PIC1/SUMO-1 , 1997, The Journal of cell biology.

[67]  C. Van Sant,et al.  Herpes simplex virus 1 alpha regulatory protein ICP0 interacts with and stabilizes the cell cycle regulator cyclin D3 , 1997, Journal of virology.

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[71]  R. Jordan,et al.  Activation of gene expression by herpes simplex virus type 1 ICP0 occurs at the level of mRNA synthesis , 1997, Journal of virology.

[72]  G. Maul,et al.  Human Cytomegalovirus Immediate Early Interaction with Host Nuclear Structures: Definition of an Immediate Transcript Environment , 1997, The Journal of cell biology.

[73]  N. DeLuca,et al.  The herpes simplex virus immediate-early protein ICP0 affects transcription from the viral genome and infected-cell survival in the absence of ICP4 and ICP27 , 1997, Journal of virology.

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[75]  E. Yeh,et al.  Preferential Modification of Nuclear Proteins by a Novel Ubiquitin-like Molecule* , 1997, The Journal of Biological Chemistry.

[76]  M. Dasso,et al.  RanBP2 associates with Ubc9p and a modified form of RanGAP1. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[77]  H. de Thé,et al.  Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[78]  F. Melchior,et al.  A Small Ubiquitin-Related Polypeptide Involved in Targeting RanGAP1 to Nuclear Pore Complex Protein RanBP2 , 1997, Cell.

[79]  L. Dick,et al.  Mechanistic Studies on the Inactivation of the Proteasome by Lactacystin in Cultured Cells* , 1997, The Journal of Biological Chemistry.

[80]  R. Everett,et al.  A novel ubiquitin‐specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein , 1997, The EMBO journal.

[81]  G. Blobel,et al.  A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex , 1996, The Journal of cell biology.

[82]  S. Lees-Miller,et al.  Attenuation of DNA-dependent protein kinase activity and its catalytic subunit by the herpes simplex virus type 1 transactivator ICP0 , 1996, Journal of virology.

[83]  P. Freemont,et al.  PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia. , 1996, Oncogene.

[84]  G. Maul,et al.  The periphery of nuclear domain 10 (ND10) as site of DNA virus deposition , 1996, The Journal of cell biology.

[85]  S. Ōmura,et al.  Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway. , 1996, Cancer research.

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[87]  R. Everett,et al.  Nuclear domain 10 as preexisting potential replication start sites of herpes simplex virus type-1. , 1996, Virology.

[88]  M. Weitzman,et al.  Adenovirus replication is coupled with the dynamic properties of the PML nuclear structure. , 1996, Genes & development.

[89]  E. Yu,et al.  Nuclear domain 10 (ND10) associated proteins are also present in nuclear bodies and redistribute to hundreds of nuclear sites after stress , 1995, Journal of cellular biochemistry.

[90]  G. Wilkinson,et al.  Disruption of PML-associated nuclear bodies during human cytomegalovirus infection. , 1995, The Journal of general virology.

[91]  P. Schaffer,et al.  An activity specified by the osteosarcoma line U2OS can substitute functionally for ICP0, a major regulatory protein of herpes simplex virus type 1 , 1995, Journal of virology.

[92]  A. Dejean,et al.  Targeting of adenovirus E1A and E4-ORF3 proteins to nuclear matrix- associated PML bodies , 1995, The Journal of cell biology.

[93]  G. Maul,et al.  Molecular characterization of NDP52, a novel protein of the nuclear domain 10, which is redistributed upon virus infection and interferon treatment , 1995, The Journal of cell biology.

[94]  R. Everett,et al.  Separation of sequence requirements for HSV-1 Vmw110 multimerisation and interaction with a 135-kDa cellular protein. , 1995, Virology.

[95]  K. Wilkinson.  Roles of ubiquitinylation in proteolysis and cellular regulation. , 1995, Annual review of nutrition.

[96]  M. Hochstrasser.  Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. , 1995, Current opinion in cell biology.

[97]  R. Everett,et al.  HSV‐1 IE protein Vmw110 causes redistribution of PML. , 1994, The EMBO journal.

[98]  R. Everett,et al.  The nuclear location of PML, a cellular member of the C3HC4 zinc-binding domain protein family, is rearranged during herpes simplex virus infection by the C3HC4 viral protein ICP0. , 1994, The Journal of general virology.

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[100]  N. Stuurman,et al.  The t(15;17) translocation alters a nuclear body in a retinoic acid‐reversible fashion. , 1994, The EMBO journal.

[101]  R. Evans,et al.  A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein , 1994, Cell.

[102]  Maria Carmo-Fonseca,et al.  Retinoic acid regulates aberrant nuclear localization of PML-RARα in acute promyelocytic leukemia cells , 1994, Cell.

[103]  R. Everett,et al.  A truncated form of herpes simplex virus type 1 immediate-early protein Vmw110 is expressed in a cell type dependent manner. , 1993, Virology.

[104]  G. Maul,et al.  Modification of discrete nuclear domains induced by herpes simplex virus type 1 immediate early gene 1 product (ICP0). , 1993, The Journal of general virology.

[105]  P. Schaffer,et al.  The herpes simplex virus type 1 regulatory protein ICP0 enhances virus replication during acute infection and reactivation from latency , 1993, Journal of virology.

[106]  M. Dasso,et al.  RCC1, a regulator of mitosis, is essential for DNA replication , 1992, Molecular and cellular biology.

[107]  F. Lo Coco,et al.  Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia. , 1992, The EMBO journal.

[108]  B. Humbel,et al.  A monoclonal antibody recognizing nuclear matrix-associated nuclear bodies. , 1992, Journal of cell science.

[109]  P. Chambon,et al.  Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins. , 1992, The EMBO journal.

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[111]  Christine Chomienne,et al.  The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR , 1991, Cell.

[112]  K. Umesono,et al.  Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML , 1991, Cell.

[113]  P. Schaffer,et al.  A cellular function can enhance gene expression and plating efficiency of a mutant defective in the gene for ICP0, a transactivating protein of herpes simplex virus type 1 , 1991, Journal of virology.

[114]  C. Ascoli,et al.  Identification of a novel nuclear domain , 1991, The Journal of cell biology.

[115]  R. Everett.  Functional and genetic analysis of the role of Vmw110 in herpes simplex virus replication , 1991 .

[116]  C. Smythe,et al.  Systems for the study of nuclear assembly, DNA replication, and nuclear breakdown in Xenopus laevis egg extracts. , 1991, Methods in cell biology.

[117]  S. Silverstein,et al.  Reactivation of latent herpes simplex virus by adenovirus recombinants encoding mutant IE-0 gene products , 1990, Journal of virology.

[118]  R. Everett,et al.  Herpes simplex virus type 1 immediate-early protein Vmw110 reactivates latent herpes simplex virus type 2 in an in vitro latency system , 1989, Journal of virology.

[119]  R. Everett.  Construction and characterization of herpes simplex virus type 1 mutants with defined lesions in immediate early gene 1. , 1989, The Journal of general virology.

[120]  K. Tyler,et al.  Immediate-early regulatory gene mutants define different stages in the establishment and reactivation of herpes simplex virus latency , 1989, Journal of virology.

[121]  P. Schaffer,et al.  Deletion mutants in the gene encoding the herpes simplex virus type 1 immediate-early protein ICP0 exhibit impaired growth in cell culture , 1987, Journal of virology.

[122]  N. Stow,et al.  Isolation and characterization of a herpes simplex virus type 1 mutant containing a deletion within the gene encoding the immediate early polypeptide Vmw110. , 1986, The Journal of general virology.