Richard E. Lloyd, Ph.D.
Department of Molecular Virology & Microbiology
Control of Translation in Virus Infection and Cell Stress
Major projects in Dr. Lloyd's lab center on mechanisms of translation control in mammalian cells. Enteroviruses such as poliovirus and coxsackievirus shut off cap-dependent protein synthesis (translation) within two hours of infection while allowing cap-independent translation of mRNAs containing IRES elements to continue. Cap-dependent translation is used to produce 95 percent of all cellular proteins, and the loss of protein homeostasis in the cell is a major cause of cell death. We have shown that enteroviral 2A protease (2Apro) and 3C protease (3Cpro) are viral proteins required for translation shutoff by cleaving key translation factors eIF4G and poly(A) binding protein (PABP). Cleavage of eIF4G destroys its ability to function in cap-dependent translation initiation. Cleavage of PABP severs the C-terminal domain of PABP in a region whose function has not been precisely determined, but regulates ribosome termination, re-initiation and mRNA stability. Work is continuing to determine the precise function of 5´-3´ interactions and the role of PABP and eIF4G in translation regulation, ribosome recycling from 3’ stop codons to 5’ start codons, polysome assembly and its topological structure.
We are also interested in mechanisms that regulate RNA Stress Granule (SG) and Processing Body (P-body) formation in cells. These two types of RNA granules aggregate translationally-silenced mRNAs and function as an extension of translation regulation and are key structures that regulate the mRNA cycle. Translational silencing by microRNAs is thought to regulate expression of about 50 percent of human genes, and function by through the SG and P-body pathways. We found that poliovirus 3Cpro cleaves a protein called G3BP that is critical for nucleating SG formation. We have also shown that Processing Bodies (PBs) are disrupted in virus-infected cells and are currently focusing on virus-induced degradation of three key components of PBs, Xrn1, Dcp1a and PAN3, all of which regulate mRNA decay in cells. Though we use a virus model system, much of our work also centers on regulation mechanisms in uninfected cells to determine how G3BP actually regulates stress granule formation, and what the mechanisms of RNA granule nucleation are. Recent work in this area has shown us that G3BP nucleation of stress granules activates PKR, resulting in phosphorylation of eIF2alpha and activation of NF-kB and JNK signal pathways. This demonstrates that cellular stress responses interface with innate immune pathways to form an integrated stress response that senses virus infection in new ways.
The Lloyd lab is also involved in two new large multi-investigator projects that seek to determine the cause of Type 1 diabetes (T1D). A large body of evidence has implicated type B enteroviruses such as Coxsackie B4 virus as a trigger or etiology driving autoimmune dysfunction that causes diabetes. Dr. Lloyd has assumed a major role in the Network for Pancreatic Organ Donors Virus Working group (nPOD-V), a consortium of international investigators collaborating on coordinated analysis of pancreas and other tissues from persons with T1D. Dr. Lloyd, together with Dr. Joe Petrosino in the MVM Department and BCM Center for Microbiome and Metagenetics are also collaborating on a much larger clinical project, the TEDDY study directed by NIDDK. TEDDY seeks to determine the environmental trigger(s) for development of T1D, and we are beginning the largest microbiome study attempted to date and the most detailed virome project attempted, involving 17,000 human samples.
Department of Molecular Virology & Microbiology
Baylor College of Medicine
One Baylor Plaza, MS BCM385
Houston, TX, 77030, U.S.A.
Ph.D. - University of Texas Medical Branch
Postdoctoral - University of Utah Medical Center
Awards, Appointments and Honors
Fellow, American Academy of Microbiology (elected), 2013
J.M. Bonderoff and R.E. Lloyd. 2010. Time-dependent Increase in Ribosome Processivity. Nucleic Acids Res. 38:7054-67. PMCID 2978347. This was a featured article (top 5%).
Suo, J., S.J. Snider, G. Mills, C.J. Creighton, R. Schiff, R. E. Lloyd, and E.C. Chang. 2010. Int6 regulates both proteasomal degradation and translation initiation and is critical for proper formation of acini by human mammary epithelium. Oncogene. Epub Oct4, 2010. PMCID: PMC3017639.
Dougherty, J.D., J.P. White and R.E.Lloyd. 2011. Poliovirus mediated disruption of cytoplasmic processing bodies. J. Virol. 85: 64-75. PMCID: PMC3014174.
Hoeffer, C.A, K.K. Cowansage, E.C. Arnold, J.L. Banko, N.J. Moerke, R.Rodriguez, E.K. Schmidt, E. Klosi, M. Chorev, R.E. Lloyd, P.Pierre, G.Wagner, J.E. LeDoux and E. Klann. 2011. Inhibition of the Interactions Between Eukaryotic Initiation Factors eIF4E and eIF4G Impairs Long-term Associative Memory Consolidation but not Reconsolidation. PNAS. Epub Feb 2. PMCID: PMC3044415
White, J.P., L.C. Reineke and R.E. Lloyd. 2011. Poliovirus IRES-mediated translation switches to an eIF2-independent mode during infection. J. Virol. 85:8884-93. PMCID: PMC3165854. Article selected for JVI “Spotlight”.
White, J.P., and R.E. Lloyd. 2011. Poliovirus unlinks TIA1 aggregation and mRNA stress granule formation. J. Virol.85:12442-54. PMCID: PMC3209409.
Reineke, L.C., and R.E. Lloyd. 2011. Animal virus schemes for translation dominance. Curr. Opinion. Virology. 1:363-372. PMCID: PMC3272495
White, J.P. and R.E. Lloyd. 2012 Regulation of Stress Granules in Virus Systems. Trends in Microbiology. 20: 175-183. PMCID: PMC3322245
Lloyd, R.E. 2012. How do viruses interact with RNA granules? PlosPathogens. 8(6): e1002741. doi:10.1371/ journal.ppat.1002741. PMCID: PMC3386173.
Reineke, L.C., Jon D. Dougherty, Philippe Pierre and R.E. Lloyd. 2012. Large G3BP-induced stress granules trigger eIF2a phosphorylation. Mol Biol. Cell. 23:3499-510. Jul 25. PMCID: PMC3442399.
Reineke, L.C. and R.E. Lloyd. 2013. Diversion of Stress Granules and P-Bodies During Viral Infection. Virology. 436:255-267.PMID: 23290869, PMCID in process.