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Selective inhibition of nuclear steroid receptor function by a protein from a human tumorigenic poxvirus
N Chen1, T Baudino, P N MacDonald
1Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, St. Louis, Missouri 63104, USA.
Abstract:
The poxvirus molluscum contagiosum (MC) has a worldwide distribution and its prevalence is on the rise. Here we report that the MCV MC013L protein inhibits glucocorticoid and vitamin D, but not retinoid or estrogen, nuclear receptor transactivation. A direct interaction of MC013L with glucocorticoid and vitamin D receptor is supported by yeast two-hybrid, GST pull-down, and far Western blot analyses. Glucocorticoids act as potent inhibitors of keratinocyte proliferation, while vitamin D and retinoids promote and block terminal differentiation, respectively. Therefore, MC013L may promote efficient virus replication by blocking the differentiation of infected keratinocytes. MC013L may be the first member of a new class of poxvirus proteins that directly modulate nuclear receptor-mediated transcription.
Insights
Molluscum contagiosum virus protein MC013L blocks vitamin D and glucocorticoid receptors, potentially aiding viral replication by inhibiting keratinocyte differentiation. This discovery introduces a new class of poxvirus proteins modulating nuclear receptors.
Area of Science:
- Virology
- Molecular Biology
- Dermatology
Background:
- Molluscum contagiosum (MC) is a widespread viral infection with increasing prevalence.
- The virus, molluscum contagiosum virus (MCV), utilizes various proteins to manipulate host cell functions for replication.
Purpose of the Study:
- To investigate the interaction of MCV protein MC013L with host nuclear receptors.
- To elucidate the role of MC013L in modulating keratinocyte differentiation and its implications for MCV replication.
Main Methods:
- Yeast two-hybrid assays to detect protein-protein interactions.
- GST pull-down assays to confirm direct binding.
- Far Western blot analysis to validate interactions.
- Analysis of nuclear receptor transactivation inhibition.
Main Results:
- MCV MC013L protein directly interacts with glucocorticoid receptor (GR) and vitamin D receptor (VDR).
- MC013L inhibits transactivation mediated by GR and VDR, but not by retinoid or estrogen receptors.
- Glucocorticoids inhibit keratinocyte proliferation; Vitamin D and retinoids regulate differentiation.
Conclusions:
- MC013L may promote MCV replication by blocking keratinocyte differentiation through inhibition of GR and VDR signaling.
- MC013L represents a novel class of poxvirus proteins that directly modulate nuclear receptor-mediated transcription.