The ND10 Component Promyelocytic Leukemia Protein Relocates to Human Papillomavirus Type 1 E4 Intranuclear Inclusion Bodies in Cultured Keratinocytes and in Warts

S. Roberts, M. L. Hillman, G. L. Knight, P. H. Gallimore

Research output: Contribution to journalArticle

Abstract

Human papillomavirus type 1 (HPV1) E4 protein is associated with cytoplasmic and nuclear inclusions in
productively infected keratinocytes. Here we have used transient expression of HPV1 E4 (also known as
E1^E4) protein in keratinocytes to reproduce formation of E4 inclusions. Immunofluorescence analysis
showed that progressive formation of inclusions correlated with diminished colocalization between E4 and
keratin intermediate filaments (IFs). Our results support a model in which the HPV1 E4-keratin IF association
is transient, occurring only at an early stage of inclusion formation. We also demonstrate that E4 induces
relocation of the promyelocytic leukemia protein (PML) from multiple intranuclear speckles (ND10 bodies) to
the periphery of nuclear E4 inclusions and that this activity is specific to full-length E4 protein. Analysis of
HPV1-induced warts demonstrated that nuclear PML-E4 inclusions were present in productively infected
keratinocytes, indicating that reorganization of PML occurs during the virus’s replication cycle. It has been
suggested that ND10 bodies are the sites for papillomavirus genome replication and virion assembly. Our
finding that E4 induces reorganization of ND10 bodies in vitro and in vivo is further strong evidence that these
domains play an important role in the papillomavirus life cycle. This study indicates that HPV1 is analogous
to other DNA viruses that disrupt or reorganize ND10 domains, possibly to increase efficiency of virus
infection. We hypothesize that HPV1 E4-induced reorganization of PML is necessary for efficient replication
of the virus during the virus-producing phase.
Original languageEnglish
Pages (from-to)673-684
JournalJournal of Virology
Volume77
Issue number1
DOIs
Publication statusPublished - 1 Jan 2003

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nuclear inclusions
Intranuclear Inclusion Bodies
warts
Warts
Papillomaviridae
keratinocytes
leukemia
Keratinocytes
Intermediate Filaments
proteins
intermediate filaments
Type I Keratin
Viruses
Proteins
DNA Viruses
Inclusion Bodies
Nuclear Proteins
Life Cycle Stages
Virion
cytoplasmic inclusions

Cite this

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title = "The ND10 Component Promyelocytic Leukemia Protein Relocates to Human Papillomavirus Type 1 E4 Intranuclear Inclusion Bodies in Cultured Keratinocytes and in Warts",
abstract = "Human papillomavirus type 1 (HPV1) E4 protein is associated with cytoplasmic and nuclear inclusions inproductively infected keratinocytes. Here we have used transient expression of HPV1 E4 (also known asE1^E4) protein in keratinocytes to reproduce formation of E4 inclusions. Immunofluorescence analysisshowed that progressive formation of inclusions correlated with diminished colocalization between E4 andkeratin intermediate filaments (IFs). Our results support a model in which the HPV1 E4-keratin IF associationis transient, occurring only at an early stage of inclusion formation. We also demonstrate that E4 inducesrelocation of the promyelocytic leukemia protein (PML) from multiple intranuclear speckles (ND10 bodies) tothe periphery of nuclear E4 inclusions and that this activity is specific to full-length E4 protein. Analysis ofHPV1-induced warts demonstrated that nuclear PML-E4 inclusions were present in productively infectedkeratinocytes, indicating that reorganization of PML occurs during the virus’s replication cycle. It has beensuggested that ND10 bodies are the sites for papillomavirus genome replication and virion assembly. Ourfinding that E4 induces reorganization of ND10 bodies in vitro and in vivo is further strong evidence that thesedomains play an important role in the papillomavirus life cycle. This study indicates that HPV1 is analogousto other DNA viruses that disrupt or reorganize ND10 domains, possibly to increase efficiency of virusinfection. We hypothesize that HPV1 E4-induced reorganization of PML is necessary for efficient replicationof the virus during the virus-producing phase.",
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The ND10 Component Promyelocytic Leukemia Protein Relocates to Human Papillomavirus Type 1 E4 Intranuclear Inclusion Bodies in Cultured Keratinocytes and in Warts. / Roberts, S.; Hillman, M. L.; Knight, G. L.; Gallimore, P. H.

In: Journal of Virology, Vol. 77, No. 1, 01.01.2003, p. 673-684.

Research output: Contribution to journalArticle

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N2 - Human papillomavirus type 1 (HPV1) E4 protein is associated with cytoplasmic and nuclear inclusions inproductively infected keratinocytes. Here we have used transient expression of HPV1 E4 (also known asE1^E4) protein in keratinocytes to reproduce formation of E4 inclusions. Immunofluorescence analysisshowed that progressive formation of inclusions correlated with diminished colocalization between E4 andkeratin intermediate filaments (IFs). Our results support a model in which the HPV1 E4-keratin IF associationis transient, occurring only at an early stage of inclusion formation. We also demonstrate that E4 inducesrelocation of the promyelocytic leukemia protein (PML) from multiple intranuclear speckles (ND10 bodies) tothe periphery of nuclear E4 inclusions and that this activity is specific to full-length E4 protein. Analysis ofHPV1-induced warts demonstrated that nuclear PML-E4 inclusions were present in productively infectedkeratinocytes, indicating that reorganization of PML occurs during the virus’s replication cycle. It has beensuggested that ND10 bodies are the sites for papillomavirus genome replication and virion assembly. Ourfinding that E4 induces reorganization of ND10 bodies in vitro and in vivo is further strong evidence that thesedomains play an important role in the papillomavirus life cycle. This study indicates that HPV1 is analogousto other DNA viruses that disrupt or reorganize ND10 domains, possibly to increase efficiency of virusinfection. We hypothesize that HPV1 E4-induced reorganization of PML is necessary for efficient replicationof the virus during the virus-producing phase.

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