Britt A Glaunsinger

Assistant Professor
Ph.D.  Molecular Virology and Microbiology    Baylor College of Medicine, 2001
B.S.   Molecular and Cellular Biology    University of Arizona, 1995

371A Koshland Hall
Berkeley, California 94720
glaunsinger@berkeley.edu
office: 510-642-5427   lab: 510-642-5273   fax:  510-642-4995

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Viruses are masterful adversaries, as they have evolved the most efficient means possible to appropriate or evade nearly every imaginable cellular pathway. We are very interested in decoding such virus:host interactions to pinpoint key events in the regulation cellular gene expression. Our principal model is the most recently discovered human herpesvirus, KSHV, which is the etiologic agent of several AIDS-associated neoplasms including Kaposi’s sarcoma.

KSHV induces a very striking phenotype upon lytic infection of human cells: the majority cellular gene expression is halted, as the host transcriptome is essentially destroyed via mRNA degradation. The magnitude of cellular transcript loss is significant; nearly 75% of all messages are massively downregulated, with another 20% undergoing more modest decreases. We have pinpointed a single viral factor to be responsible for this ‘host shutoff’ phenotype. Particularly intriguing for us is that this protein, named SOX, appears to lack intrinsic ribonuclease activity and therefore must presumably hijack cellular machinery to promote RNA destruction.

Control of mRNA stability is known to a play vital role in tightly regulating expression of individual genes, ensuring the fidelity of transcription and processing, and navigating cellular responses to stress. However, how these processes and pathways are orchestrated in mammalian cells remains an open and important question. Our lab seeks to gain insight into these events by revealing how KSHV and its viral SOX protein interface with the cellular RNA processing and turnover machinery. In addition, we are exploring the contribution of host shutoff to the viral lifecycle and its role in viral evasion of the host immune response.

A second avenue of research in the lab is to understand selective evasion of the virus-induced message turnover. In particular, do viral messages themselves evade destruction, especially given that they are transcribed and processed with the same cellular machinery used for the host genes? Furthermore, select cellular messages remain highly expressed during the viral lytic cycle and appear to be resistant to destruction by SOX. We hypothesize that KSHV may have evolved specific means of allowing continued expression of genes with key roles in the viral lifecycle; thus, we are investigating both the mechanism(s) of evasion and the contributions of these genes to KSHV replication. We anticipate that these studies may reveal novel RNA stability elements and/or pinpoint circumstances under which deviation from the normal pathway to degradation can occur.

Covarrubias S, Richner JM, Clyde K, Lee YJ, Glaunsinger BA. Host shutoff is a conserved phenotype of gammaherpesvirus infection and is orchestrated exclusively from the cytoplasm. J Virol. 2009 Sep;83(18):9554-66

Lee YJ, Glaunsinger BA. Aberrant herpesvirus-induced polyadenylation correlates with cellular messenger RNA destruction. PLoS Biol. 2009 May 5;7(5):e1000107 PDF

Martin Rowe*, Britt Glaunsinger*, Daphne van Leeuwen*, Jianmin Zuo, David Sweetman, Don Ganem, Jaap Middeldorp, Emmanuel J. H. J. Wiertz, and Maaike E. Ressing. Host shutoff during productive Epstein-Barr virus infection is mediated by BGLF5 and may contribute to immune evasion. PNAS (2007) 104(9):3366-71. *co-first authors PDF

Glaunsinger B and Ganem D. (2006) Messenger RNA Turnover and its Regulation in Herpesviral Infection. Advances in Virus Research. 66: 337-394. Abstract

Glaunsinger B, Chavez L, Ganem D. The exonuclease and host shutoff functions of the SOX protein of Kaposi's sarcoma-associated herpesvirus are genetically separable. J Virol. 2005 Jun;79(12):7396-401. PDF

Glaunsinger B, Ganem D. Highly selective escape from KSHV-mediated host mRNA shutoff and its implications for viral pathogenesis. J Exp Med. 2004 Aug 2 Vol. 200(3):391-8. PDF

Glaunsinger B, Ganem D. Lytic KSHV infection inhibits host gene expression by accelerating global mRNA turnover. Mol Cell. 2004 Mar 12;13(5):713-23. PDF

Frese KK, Lee SS, Thomas DL, Latorre IJ, Weiss RS, Glaunsinger BA, Javier RT. Selective PDZ protein-dependent stimulation of phosphatidylinositol 3-kinase by the adenovirus E4-ORF1 oncoprotein. Oncogene. 2003 Feb 6;22(5):710-21.

Glaunsinger BA, Weiss RS, Lee SS, Javier R. Link of the unique oncogenic properties of adenovirus type 9 E4-ORF1 to a select interaction with the candidate tumor suppressor protein ZO-2. EMBO J. 2001 Oct 15;20(20):5578-86.

Thomas M, Glaunsinger B, Pim D, Javier R, Banks L. HPV E6 and MAGUK protein interactions: determination of the molecular basis for specific protein recognition and degradation. Oncogene. 2001 Sep 6;20(39):5431-9.

Glaunsinger BA, Lee SS, Thomas M, Banks L, Javier R. Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins. Oncogene. 2000 Nov 2;19(46):5270-80.

Lee SS, Glaunsinger B, Mantovani F, Banks L, Javier RT. Multi-PDZ domain protein MUPP1 is a cellular target for both adenovirus E4-ORF1 and high-risk papillomavirus type 18 E6 oncoproteins. J Virol. 2000 Oct;74(20):9680-93.

Gardiol D, Kuhne C, Glaunsinger B, Lee SS, Javier R, Banks L. Oncogenic human papillomavirus E6 proteins target the discs large tumour suppressor for proteasome-mediated degradation. Oncogene. 1999 Sep 30;18(40):5487-96.

Nelson DE, Glaunsinger B, Bohnert HJ. Abundant accumulation of the calcium-binding molecular chaperone calreticulin in specific floral tissues of Arabidopsis thaliana. Plant Physiol. 1997 May;114(1):29-37.