|
University of California, San Francisco
533 Parnassus Avenue
Box 0703
San Francisco, CA. 94143-0703
TEL: 415-502-1905
FAX: 415-502-1901
E.Mail: matija@itsa.ucsf.edu
Link to Peterlin Lab: www.ucsf.edu/bmplab
Dr. Peterlin received his MD from Harvard Medical School, obtained his clinical training in internal medicine and rheumatology at Stanford U. Medical School and his research training with Drs. Phillip Leder and Jacob V. Maizel, Jr. at the NIH and Hugh O. McDevitt at Stanford. He received the Alexander von Humboldt Prize and is an Honorary Professor at the U. of Ljubljana, Slovenia.
Research summary:
We are interested in the molecular biology of severe combined immunodeficiencies, be they genetic (BLS) or acquired (AIDS). Interestingly, these studies led to new models of human organ-specific autoimmune diseases in the mouse. Along the way, we touched on many aspects of transcription, cellular signaling, and retroviral replication. Fundamental insights with important consequences for eukaryotic biology have been forthcoming.
As a fellow in rheumatology, I described a variant of the bare lymphocyte syndrome, where B lymphocytes lack major histocompatibility complex (MHC) class I, II or both determinants on the cell surface. Affected children have severe combined immunodeficiency, fail to thrive and die early. Their only hope is genetic reconstitution. The subsequent twenty year long search defined four complementation groups of this disorder, revealed mutations in the four affected genes, and defined how complex regulatory transcriptional networks assemble and function. Moreover, by introducing one of these regulatory factors, the class II transactivator (CIITA), we can convert any cell into a professional antigen presenting cell. This finding has implications for models of autoimmunity, cancer immunotherapy and vaccine development. Moreover, we can now also turn off deleterious immune responses, which could ameliorate autoimmune diseases.
AIDS is a common severe combined immunodeficiency. In the eighties, we demonstrated how HIV replicates in the body, how transcription is activated by NF-kB and how it is transactivated by Tat. Furthermore, we demonstrated that HIV can establish a latent reservoir and defined strategies of purging the provirus from the infected host. Studies on Tat led us to discover the regulation of elongation of transcription. Although this type of transcriptional control is used extensively in bacteria, before HIV, it was ignored in the eukaryotic world. For these effects, Tat recruits P-TEFb, which contains cyclins T1, T2 or K and Cdk9. P-TEFb phosphorylates the C-terminal domain (CTD) of RNAPII and N-TEF, thus freeing RNAPII to elongate along the viral genome. The phosphorylated CTD also assembles capping enzymes, splicing factors and the polyadenylation machinery for efficient co-transcriptional processing of mRNA.
P-TEFb is a key player in eukarytic biology. We have now inactivated its three cyclin partners in the mouse and will study their function in vivo. Moreover, we know that NF-kB, CIITA, c-Myc, androgen receptors and most activators that function from enhancers function via P-TEFb. In sharp contrast, transcriptional repressors block the ability of P-TEFb to phosphorylate the RNAPII.
Studies on the viral accessory protein Nef revealed steps in the HIV replicative cycle that deal with the production and budding of new virions. We found that Nef binds the phosphoinositol 3-kinase (PI-3K) signalosome, which is composed of PI-3K, the guanine nucleotide exchange factor Vav, small GTPases Cdc42/Rac1 and p21 activated kinase PAK. This activation results in cytoskeletal rearrangements and downstream effector functions. They provide a better milieu for the production of HIV as well as aggregate lipid rafts from which new virions bud. Indeed, HIV produced in the presence of Nef contains more lipid and is more infectious. Nef also contains a cholesterol recognition motif (CRM) that carries newly synthesized cholesterol to sites of viral budding and release. These last studies have great implications for the organization of signalosomes as well as cellular and viral replication.
Representative recent publications:
Greene, W.C. and B.M. Peterlin. 2002. Charting HIV’s remarkable voyage through the cell: Basic science as a passport to future therapy. Nature Med. 8: 673-680.
Kanazawa, S., L Souchek, G. Evan and B.M. Peterlin. 2003. P-TEFb mediates transcriptional elongation and cell fates by cMyc. Oncogene 22:5707-5711.
Lin X., Yen, Y.S. Irwin, D., J. Romeo, L. Huang and B.M. Peterlin. 2003. Transcriptional profiles of latent HIV in infected individuals: Effects of Tat on the host and reservoir. J. Virol. 77:8227-8236.
Nekrep, N., N. Jabrane-Ferrat, H. Wolf, M. Eibl, M. Geyer and B.M. Peterlin. 2002. Point mutation in a winged-helix DNA-binding motif causes atypical bare lymphocyte syndrome. Nature Immunol. 3:1075-1081.
Nekrep, N., J.D. Fontes, M. Geyer and B.M. Peterlin. 2003. How the lymphocyte loses its clothes. Immunity 18:453-458.
Peterlin, B.M. and D. Trono. 2003. Hide, shield and strike back: How HIV-infected cells avoid immune eradication. Nat. Rev. Immunol. 3:97-107.
Taube, R., X. Lin, D. Irwin, K. Fujinaga, and B.M.Peterlin. 2002. Interaction between P-TEFb and C-terminal domain of RNA polymerase II activates transcription from sites upstream and downstream of target genes. Mol. Cell. Biol. 22:321-331.
Tosi, G. and B.M. Peterlin. 2002. Phosphorylation of CIITA directs its oligomerization, accumulation and increased activity on MHCII promoters. EMBO J. 21:5467-5476.
Zhang, F., M. Barboric, K.A. Blackwell, and B. M. Peterlin. 2003. A model for repression: CTD analogs and PIE-1 block transcriptional elongation by P-TEFb. Genes Dev. 17:748-758.
Zheng, Y.H., Yu, H.F. and B.M. Peterlin. 2002. Human p32 protein relieves a post-transcriptional block to HIV replication in murine cells. Nat.Cell. Biol. 5:611-618.
Zheng, Y.H., A. Plemenitas, C.J. Fielding, and B.M. Peterlin. 2003. Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions. Proc. Natl. Acad. Sci. USA 100:8460-8465.
|
