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Cancer Discov. 2018 Nov;8(11):1474-1489. doi: 10.1158/2159-8290.CD-17-1018. Epub 2018 Sep 12.

Multiple Routes to Oncogenesis Are Promoted by the Human Papillomavirus-Host Protein Network.

Author information

1
Quantitative Biosciences Institute (QBI), UCSF, San Francisco, California.
2
Gladstone Institute of Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, California.
3
Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, California.
4
Department of Medicine, UCSD, La Jolla, California.
5
The Cancer Cell Map Initiative (CCMI), UCSF and UCSD, San Francisco and La Jolla, California.
6
Department of Otolaryngology-Head and Neck Surgery, UCSF, San Francisco, California.
7
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
8
Department of Medicine, UCSD, La Jolla, California. nevan.krogan@ucsf.edu tideker@ucsd.edu.
9
Quantitative Biosciences Institute (QBI), UCSF, San Francisco, California. nevan.krogan@ucsf.edu tideker@ucsd.edu.
#
Contributed equally

Abstract

We have mapped a global network of virus-host protein interactions by purification of the complete set of human papillomavirus (HPV) proteins in multiple cell lines followed by mass spectrometry analysis. Integration of this map with tumor genome atlases shows that the virus targets human proteins frequently mutated in HPV- but not HPV+ cancers, providing a unique opportunity to identify novel oncogenic events phenocopied by HPV infection. For example, we find that the NRF2 transcriptional pathway, which protects against oxidative stress, is activated by interaction of the NRF2 regulator KEAP1 with the viral protein E1. We also demonstrate that the L2 HPV protein physically interacts with the RNF20/40 histone ubiquitination complex and promotes tumor cell invasion in an RNF20/40-dependent manner. This combined proteomic and genetic approach provides a systematic means to study the cellular mechanisms hijacked by virally induced cancers.Significance: In this study, we created a protein-protein interaction network between HPV and human proteins. An integrative analysis of this network and 800 tumor mutation profiles identifies multiple oncogenesis pathways promoted by HPV interactions that phenocopy recurrent mutations in cancer, yielding an expanded definition of HPV oncogenic roles. Cancer Discov; 8(11); 1474-89. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333.

PMID:
30209081
PMCID:
PMC6375299
[Available on 2019-11-01]
DOI:
10.1158/2159-8290.CD-17-1018

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