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Journal of Virology, September 2005, p. 11824-11836, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11824-11836.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inhibition of Ubiquitination and Stabilization of Human Ubiquitin E3 Ligase PIRH2 by Measles Virus Phosphoprotein

Mingzhou Chen,1 Jean-Claude Cortay,1 Ian R. Logan,2 Vasileia Sapountzi,2 Craig N. Robson,2 and Denis Gerlier1*

Immunité & Infections Virales, CNRS—Univ-Lyon 1 UMR 5537, IFR Laennec, 69372 Lyon Cedex 08, France,1 Northern Institute for Cancer Research, The Medical School, University of Newcastle, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom2

Received 24 February 2005/ Accepted 21 June 2005

Using a C-terminal domain (PCT) of the measles virus (MV) phosphoprotein (P protein) as bait in a yeast two-hybrid screen, a cDNA identical to the recently described human p53-induced-RING-H2 (hPIRH2) cDNA was isolated. A glutathione S-transferase-hPIRH2 fusion protein expressed in bacteria was able to pull down P protein when mixed with an extract from P-expressing HeLa cells in vitro, and myc-tagged hPIRH2 could be reciprocally coimmunoprecipitated with MV P protein from human cells. Additionally, immunoprecipitation experiments demonstrated that hPIRH2-myc, MV P, and nucleocapsid (N) proteins form a ternary complex. The hPIRH2 binding site was mapped to the C-terminal X domain region of the P protein by using a yeast two-hybrid assay. The PCT binding site was mapped on hPIRH2 by using a novel yeast two-hybrid tagged PCR approach and by coimmunoprecipitation of hPIRH2 cysteine mutants and mouse/human PIRH2 chimeras. The hPIRH2 C terminus could mediate the interaction with MV P which was favored by the RING-H2 motif. When coexpressed with an enhanced green fluorescent protein-tagged hPIRH2 protein, MV P alone or in a complex with MV N was able to redistribute hPIRH2 to outside the nucleus, within intracellular aggregates. Finally, MV P efficiently stabilized hPIRH2-myc expression and prevented its ubiquitination in vivo but had no effect on the stability or ubiquitination of an alternative ubiquitin E3 ligase, Mdm2. Thus, MV P protein is the first protein from a pathogen that is able to specifically interact with and stabilize the ubiquitin E3 ligase hPIRH2 by preventing its ubiquitination.

* Corresponding author. Mailing address: Immunité & Infections Virales, CNRS—Univ-Lyon 1 UMR 5537, IFR Laennec, 69372 Lyon Cedex 08, France. Phone: 33 (0)4 78 77 86 18. Fax: 33 (0)4 78 77 87 54. E-mail: denis.gerlier{at}laennec.univ-lyon1.fr.

Journal of Virology, September 2005, p. 11824-11836, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11824-11836.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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