A5071307291- interferon and immune responses
- RNA and protein synthesis mechanisms
- Inflammasome and immune disorders
- HIV Research and Treatment
- Plant Virus Research Studies
- Bacteriophages and microbial interactions
- RNA Research and Splicing
- Viral gastroenteritis research and epidemiology
- CRISPR and Genetic Engineering
- Evolution and Genetic Dynamics
- Influenza Virus Research Studies
- PARP inhibition in cancer therapy
- SARS-CoV-2 and COVID-19 Research
- Genetics, Aging, and Longevity in Model Organisms
- Genomics and Phylogenetic Studies
- Plant biochemistry and biosynthesis
- Immune Response and Inflammation
- RNA modifications and cancer
- Viral Infections and Immunology Research
- Enzyme Structure and Function
- Ubiquitin and proteasome pathways
- Isotope Analysis in Ecology
- Cassava research and cyanide
- Polyomavirus and related diseases
- Animal Disease Management and Epidemiology
University of California, San Diego
2016-2025
La Jolla Alcohol Research
2022
Howard Hughes Medical Institute
2006-2016
Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa
2012-2016
Fred Hutch Cancer Center
2014-2016
Cancer Research Center
2016
University of California, San Francisco
2005-2010
University of California, Berkeley
2005
Igenbio (United States)
2000-2003
The University of Texas Southwestern Medical Center
2001
Defining the gene products that play an essential role in organism's functional repertoire is vital to understanding system level organization of living cells. We used a genetic footprinting technique for genome-wide assessment genes required robust aerobic growth Escherichia coli rich media. identified 620 as and 3,126 dispensable under these conditions. Functional context analysis data allows individual assignments be refined. Evolutionary demonstrates significant tendency E. preserved...
ADP‐ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage viral infection is involved intra‐ extracellular signaling, chromatin transcriptional regulation, protein biosynthesis, cell death. ADP‐ribosylation catalyzed ADP‐ribosyltransferases (ARTs), which transfer ADP‐ribose from NAD + onto substrates. The modification, occurs as mono‐ or poly‐ADP‐ribosylation, reversible due...
ABSTRACT Novel drug targets are required in order to design new defenses against antibiotic-resistant pathogens. Comparative genomics provides opportunities for finding optimal among previously unexplored cellular functions, based on an understanding of related biological processes bacterial pathogens and their hosts. We describe integrated approach identification prioritization broad-spectrum targets. Our strategy is genetic footprinting Escherichia coli followed by metabolic context...
Post-translational protein modifications such as phosphorylation and ubiquitinylation are common molecular targets of conflict between viruses their hosts. However, the role other post-translational modifications, ADP-ribosylation, in host-virus interactions is less well characterized. ADP-ribosylation carried out by proteins encoded PARP (also called ARTD) gene family. The majority 17 human genes poorly one protein, PARP13/ZAP, has broad antiviral activity evolved under positive...
Many viruses use overprinting (alternate reading frame utilization) as a means to increase protein diversity in genomes severely constrained by size. However, the evolutionary steps that facilitate de novo generation of novel within an ancestral ORF have remained poorly characterized. Here, we describe identification gene, expressed from Alternate Large T Open (ALTO) early region Merkel cell polyomavirus (MCPyV), causative agent most carcinomas. ALTO is during, but not required for,...
The Polyomaviridae is a family of small, non-enveloped viruses with circular dsDNA genomes approximately 5 kbp. includes four genera whose members have restricted host range, infecting mammals and birds. Polyomavirus also been detected recently in fish. Merkel cell polyomavirus raccoon are associated cancer their host; other human veterinary pathogens. Clinical manifestations obvious immunocompromised patients but not healthy individuals. This summary the International Committee on Taxonomy...
Inflammasomes are cytosolic multi-protein complexes that initiate immune responses to infection by recruiting and activating the Caspase-1 protease. Human NLRP1 was first protein shown form an inflammasome, but its physiological mechanism of activation remains unknown. Recently, specific variants mouse rat were found be activated upon N-terminal cleavage anthrax lethal factor However, agonists for other variants, including human NLRP1, not known, it unclear if they also proteolysis. Here we...
The NLRP1 inflammasome is a multiprotein complex that potent activator of inflammation. Mouse NLRP1B can be activated through proteolytic cleavage by the bacterial Lethal Toxin (LeTx) protease, resulting in degradation N-terminal domains and liberation bioactive C-terminal domain, which includes caspase activation recruitment domain (CARD). However, natural pathogen-derived effectors activate human have remained unknown. Here, we use an evolutionary model to identify several proteases from...
IFIT (interferon-induced with tetratricopeptide repeats) proteins are critical mediators of mammalian innate antiviral immunity. Mouse IFIT1 selectively inhibits viruses that lack 2'O-methylation their mRNA 5' caps. Surprisingly, human does not share this specificity. Here, we resolve discrepancy by demonstrating and mouse have evolved distinct functions using a combination evolutionary, genetic virological analyses. First, show (renamed IFIT1B) orthologs, but paralogs diverged >100 mya....
Hosts have evolved diverse strategies to respond microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. Here, we find that 3CL protease (3CL pro ) encoded coronaviruses, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), cleaves a rapidly evolving region human CARD8 activates robust inflammasome response. is required for cell death release pro-inflammatory cytokines during SARS-CoV-2 infection. We...
Similar to other coronaviruses, disruption of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) NSP16 function attenuates viral replication in a type I interferon-dependent manner. In vivo , our results show reduced disease and at late times the hamster lung, but an earlier titer deficit for mutant (dNSP16) upper airway. addition, confirm role IFIT1 also demonstrate necessity IFIT3 mediating dNSP16 attenuation.
ABSTRACT In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology paramount frameworks should be reviewed periodically. Changes made with care, however, to avoid impeding science that essential for rapidly reducing responding pandemic threats as well addressing more common challenges caused by infectious diseases. Decades uniquely positioned US able respond COVID-19 crisis astounding speed, delivering life-saving vaccines...
Protein post-translational modifications (PTMs) are an important battleground in the evolutionary arms races that waged between host innate immune system and viruses. One such PTM, ADP-ribosylation, has recently emerged as mediator of antiviral immunity. Important for host–virus conflict over this PTM is addition ADP-ribose by PARP proteins removal macrodomain-containing proteins. Interestingly, several proteins, known macroPARPs, contain macrodomains well a domain, these both response...
To address questions regarding the mechanism of serine protease catalysis, we have solved two X-ray crystal structures α-lytic (αLP) that mimic aspects transition states: αLP at pH 5 (0.82 Å resolution) and bound to peptidyl boronic acid inhibitor, MeOSuc-Ala-Ala-Pro-boroVal (0.90 resolution). Based on these structures, there is no evidence of, or requirement for, histidine-flipping during acylation step reaction. Rather, our data suggests upon protonation His57, Ser195 undergoes a...
RNA is a crucial structural component of many ribonucleoprotein (RNP) complexes, including the ribosome, spliceosome, and signal recognition particle, but role in guiding complex formation only beginning to be explored. In case HIV, viral replication requires assembly an RNP composed Rev protein homooligomer response element (RRE) mediate nuclear export unspliced mRNAs. Assembly functional Rev-RRE proceeds by cooperative oligomerization on RRE scaffold utilizes both protein-protein...