Mohr Lab - Microbiology

Mohr
Ian Mohr, Ph.D.
Professor, Department of Microbiology

Medical Science Building, Room 214

550 First Avenue, New York, NY 10016
Office: (212) 263-0415
Fax: (212) 263-8276
Email: ian.mohr@med.nyu.edu

 

 

BIOGRAPHIC DETAILS:

Graduate Education:

 

Dr. Mohr was a graduate student at Cold Spring Harbor Laboratory and received his Ph.D. degree from the State University of New York, Stony Brook in 1989.

Postdoctoral Training:

Dr. Mohr was a Postdoctoral Fellow in the Department of Molecular and Cell Biology, Division of Biochemistry and Molecular Biology at the University of California, Berkeley.

Academic Appointments:

Professor of Microbiology

 

RESEARCH INTERESTS:

MohrFig1            My lab is interested in the interactions between viruses and their cellular hosts that are important for regulating protein synthesis. This represents a critical step in the viral lifecycle as all viruses remain completely reliant on host protein synthetic functions to produce the polypeptides required for their replication. In particular, viruses must recruit host ribosomes to translate their mRNAs. For viruses that produce capped, polyadenylated mRNAs like herpesviruses and poxviruses, this involves gaining control of eIF4F, a key multisubunit cellular translation initiation factor. Composed of the cap binding protein eIF4E, the large molecular scaffold eIF4G, and the eIF4A RNA unwinding enzyme, eIF4F recognizes the 7-methyl GTP cap structure at the 5’ end of the mRNA and recruits the 40S ribosome via an association between eIF3 and eIF4G (fig 1). Finally, the cellular polyadenylate binding protein (PABP), while itself not a component of eIF4F, physically interacts with eIF4G bridging the 5’and 3’ ends of the mRNA. The activity of eIF4F is regulated in part by the 4E-BP1 translational repressors that bind eIF4E and prevent it from associating with eIF4G. Phosphorylation of 4E-BP1 by the cellular kinase mTORC1 results in the release of eIF4E, which can now in turn associate with eIF4G and assemble the eIF4F complex. In addition, an eIF4F-associated kinase (Mnk1), binds eIF4G and phosphorylates eIF4E, stimulating translation. Importantly, herpesviruses and poxviruses all stimulate inactivation of the translational repressor 4E-BP1, eIF4F assembly, and phosphorylation of eIF4E. Remarkably, they achieve this common goal through different molecular mechanisms. Much of the work in the lab is directed to understand the underlying molecular mechanisms through which these viruses control eIF4F. For example, HSV-1 encodes a ser/thr kinase (Us3) that stimulates mTORC1 and an eIF4G-binding protein (ICP6) that promotes binding of eIF4E to eIF4G. Cytomegalovirus, which belongs to a different herpesvirus subfamily, stimulates the infected host cell to raise the intracellular concentration of translation initiation factors. Finally, poxviruses, which replicate in the cytoplasm, utilize yet another strategy to recruit and concentrate initiation factors in viral replication factories.

            We are also part of a larger collaborative effort here at NYU (involving the labs of Moses Chao & Angus Wilson) to understand HSV1 latency in neurons. To achieve this goal, we have developed a primary neuron cell culture system capable of supporting a stable, nonproductive HSV1 infection that faithfully exhibits key hallmarks of latency defined in animal models, including nuclear LAT accumulation and the absence of detectable lytic gene expression. Reactivation in living neurons can be scored in real-time using a GFP-reporter virus, requires key viral gene products defined in vivo, and its dependence on specific neuronal functions interrogated using selective small molecule inhibitors, biologicals, or RNAi gene-silencing techniques. Using this system, we have established that i) neuronal PI-3 kinase /Akt signaling is required to suppress HSV productive (lytic) growth and maintain latency; and ii) disrupting this signaling pathway, even transiently, triggers reactivation. This directly demonstrates that principal features of latency can be reconstituted by infecting pure neuronal cultures with HSV-1 and illustrates that a pivotal neuron-specific signal-transduction pathway is a critical regulator of the virus. Importantly, these findings suggest that neuronal targets of PI3-K/Akt signaling are the likely cellular effectors responsible for maintaining latency, paving the way to understand how alterations to these cellular targets may transmit the initial reactivation signal (s) to the repressed viral genome, a major unresolved puzzle in virology. One of these targets is mTORC1, a major intracellular sensor of oxygen, nutrient, growth factor, and energy availability. mTORC1 also controls cap-dependent translation in neurons by inactivating the 4E-BP1 repressor.  Present work in the lab is directed to understand precisely how mTORC1 regulates latency and the role of translational control in this process.

 

PUBLICATIONS:

Control of viral latency in neurons by axonal mTOR signaling and the 4E-BP translation repressor.
M. Kobayashi, A. C. Wilson, M. V. Chao, I. Mohr. Genes Dev. 26, 1527­1532
(2012). PMID: 22802527

Viral subversion of the host cells protein synthesis machinery.
Nat Rev Microbiol. 2011 Oct 17;9(12):860-75. doi: 10.1038/nrmicro2655. Review.
PMID:22002165

Translational control of cytoplasmic poly A binding protein (PABP) abundance in HCMV-infected cells.
Perez, C., C. McKinney, U. Chuluunbaatar and Mohr   I. (2011)
J Virol. 85: 156-164.

Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication.
Chuluunbaatar, U., R. Roller, M. Feldman, K. Shokat and Mohr   I. (2010)
Genes & Development 24: 2627-2639.

Nature and duration of growth factor signaling through receptor tyrosine kinases regulates HSV-1 latency in neurons.
Camarena, V., M. Kobayashi, J.Y. Kim, P. Roehm, R. Perez, J. Gardiner, A.C. Wilson, Mohr   I., and M.V. Chao (2010)
Cell Host & Microbe, 8: 320-330.

Activation of a host translational control pathway by a viral developmental switch.
Arias, C., D. Walsh, J. Harbell. A.C. Wilson, and Mohr   I. (2009)
PLOS Pathogens 5(3): e1000334.

Eukaryotic translation initiation factor 4F architectural alterations accompany translation initiation factor redistribution in poxvirus-infected cells.
Walsh, D., C. Arias, C. Perez, D. Halladin, M. Escandon, T. Ueda, R. Watanabe-Fukunaga, R. Fukunaga, and Mohr   I. (2008)
Mol. Cell. Biol. 28: 2648 - 2658.

Mohr I. J., T. Pe’ery and M.B. Mathews. (2007)
“Protein synthesis and Translational Control during Viral Infection” in N. Sonenberg, J. Hershey, M.B. Mathews (eds), Translational control in Biology and Medicine, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 545 - 599.

Inhibition of the cellular 2’-5’ oligoadenylate synthetase by the herpes simplex virus Us11 protein.
Sanchez, R., and Mohr   I. (2007)
J. Virol. 81: 3455 - 3464.

Maintenance of ER homeostasis in HSV-1 infected cells through the association of a viral glycoprotein with PERK, a cellular ER stress sensor.
Mulvey M. and Mohr   I. (2007)
J. Virol. 81: 3377 - 3390.

Assembly of an active translation initiation factor complex by a viral protein.
Walsh D. and Mohr I. (2006)
Genes & Development, 20: 461 - 472.

Phosphorylation of eIF4E by mnk-1 enhances HSV-1 translation and replication in quiescent cells.
Walsh D. and Mohr   I. (2004)
Genes & Development, 18: 660 - 672.

 

LAB MEMBERS:

Caleb McKinney (graduate student)
Jessica Linderman, Ph.D. (post-doc)
Heidi Karttunen, Ph.D. (post-doc)
Lora Shiflett Ph.D. (post-doc)
Hannah Burgess Ph.D. (post-doc)
Aldo Pourchet DVM Ph.D. (post-doc)