A5014882971- RNA Research and Splicing
- Nuclear Structure and Function
- interferon and immune responses
- RNA modifications and cancer
- RNA regulation and disease
- Influenza Virus Research Studies
- RNA and protein synthesis mechanisms
- Viral Infections and Immunology Research
- Virus-based gene therapy research
- RNA Interference and Gene Delivery
- SARS-CoV-2 and COVID-19 Research
- Animal Virus Infections Studies
- Malaria Research and Control
- Invertebrate Immune Response Mechanisms
- Cancer-related Molecular Pathways
- Biochemical and Molecular Research
- Enzyme Structure and Function
- Renin-Angiotensin System Studies
- Ubiquitin and proteasome pathways
- Metabolism and Genetic Disorders
- Heart Failure Treatment and Management
- Microtubule and mitosis dynamics
- Cancer Immunotherapy and Biomarkers
- MicroRNA in disease regulation
- Trypanosoma species research and implications
The University of Texas Southwestern Medical Center
2016-2025
Southwestern Medical Center
2007-2021
University of Miami
2002-2006
Sylvester Comprehensive Cancer Center
2002-2006
New York University
1992-2003
Rockefeller University
2000-2002
Howard Hughes Medical Institute
1999-2002
Kaplan (United States)
1997
Cornell University
1990-1991
Significance To successfully establish infection, viral pathogens have to overcome the interferon (IFN)-mediated antiviral response. Previous studies revealed that accessory protein Orf6 of SARS-CoV and SARS-CoV-2 is able inhibit STAT1 nuclear translocation block IFN signaling. In this study, we report localizes at pore complex (NPC) where it binds directly Nup98-Rae1 target import pathway mediate inhibition. A better understanding strategies used by viruses subvert host immune responses...
SARS-CoV-2 Nsp1 protein binds the mRNA export receptor NXF1-NXT1 to inhibit nuclear of mRNAs and promote infection.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, roles and contributions of during physiological infection remain unexplored. We assessed role using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. plays key...
The NS1 protein of influenza A virus is a major virulence factor that essential for pathogenesis. functions to impair innate and adaptive immunity by inhibiting host signal transduction gene expression, but its mechanisms action remain be fully elucidated. We show here forms an inhibitory complex with NXF1/TAP, p15/NXT, Rae1/mrnp41, E1B-AP5, which are key constituents the mRNA export machinery interact both mRNAs nucleoporins direct through nuclear pore complex. Increased levels NXF1, p15,...
The mammalian nuclear pore complex (NPC) is comprised of ∼50 unique proteins, collectively known as nucleoporins. Through fractionation rat liver nuclei, we have isolated >30 potentially novel nucleoporins and begun a systematic characterization these proteins. Here, present the Nup96, nucleoporin with predicted molecular mass 96 kD. Nup96 generated through an unusual biogenesis pathway that involves synthesis 186-kD precursor protein. Proteolytic cleavage yields two nucleoporins:...
Signal-mediated nuclear import and export proceed through the pore complex (NPC). Some NPC components, such as nucleoporins (Nups) Nup98 Nup96, are also associated with interior. is a target of vesicular stomatitis virus (VSV) matrix (M) protein–mediated inhibition messenger RNA (mRNA) export. Here, Nup96 were found to be up-regulated by interferon (IFN). M mRNA was reversed when cells treated IFN-γ or transfected complementary DNA (cDNA) encoding Nup96. Thus, increased expression...
Sporozoites, the invasive form of malaria parasites transmitted by mosquitoes, are quiescent while in insect salivary glands. Sporozoites only differentiate inside hepatocytes mammalian host. We show that sporozoite latency is an active process controlled a eukaryotic initiation factor-2α (eIF2α) kinase (IK2) and phosphatase. IK2 activity dominant gland sporozoites, leading to inhibition translation accumulation stalled mRNAs into granules. When sporozoites injected host, eIF2α phosphatase...
Abstract Nuclear pore complexes (NPCs) are important for cellular functions beyond nucleocytoplasmic trafficking, including genome organization and gene expression. This multi-faceted nature the slow turnover of NPC components complicates investigations how individual nucleoporins act in these diverse processes. To address this question, we apply an A uxin- I nduced D egron (AID) system to distinguish roles basket NUP153, NUP50 TPR. Acute depletion TPR causes rapid pronounced changes...
Influenza A virus usurps host signaling factors to regulate its replication. One example is mTOR, a cellular regulator of protein synthesis, growth and motility. While the role mTORC1 in viral infection has been studied, mechanisms that induce activation substrates regulated by during influenza have not established. In addition, mTORC2 remains unknown. Here we show PDPK1 differentially phosphorylate AKT upon infection. PDPK1-mediated phoshorylation at distinct site required for virus. On...
The Nup107-160 complex is a critical subunit of the nuclear pore. This localizes to kinetochores in mitotic mammalian cells, where its function unknown. To examine recruitment kinetochores, we stained human cells with antisera four components. Each antibody not only but also prometaphase spindle poles and proximal fibers, mirroring dual localization checkpoint proteins Mad1, Mad2, Bub3, Cdc20. Indeed, expanded crescents encircled unattached similar hyperaccumulation observed dynamic outer...
In response to environmental stresses, the mammalian serine threonine kinases PERK, GCN2, HRI, and PKR phosphorylate regulatory 51 of eukaryotic translation initiation factor 2α (eIF2α) inhibit global protein synthesis. Plasmodium , protozoan that causes malaria, expresses three eIF2α kinases: IK1, IK2, PK4. Like IK1 regulates stress amino acid starvation. IK2 inhibits development malaria sporozoites present in mosquito salivary glands. Here we show phosphorylation by PK4 59 is essential for...
Influenza A virus is a major human pathogen with genome comprised of eight single-strand, negative-sense, RNA segments. Two viral segments, NS1 and M, undergo alternative splicing yield several proteins including NS1, NS2, M1 M2 proteins. However, the mechanisms or players involved in these segments have not been fully studied. Here, by investigating interacting partners function cellular protein NS1-binding (NS1-BP), we revealed novel segment. Using proteomics approach, identified complex...
Abstract Three of the eight RNA segments encoded by influenza A virus (IAV) undergo alternative splicing to generate distinct proteins. Previously, we found that host proteins hnRNP K and NS1-BP regulate IAV M segment splicing, but mechanistic details were unknown. Here show bind mRNA downstream M2 5′ splice site (5′ss). binds most proximal 5′ss, partially overlapping U1 snRNP binding site, while further promotes recruitment. Mutation either or both NS1-BP-binding sites results in...
Viral infection induces the expression of numerous host genes that impact outcome infection. Here, we show human lung epithelial cells with influenza A virus (IAV) also a broad program alternative splicing genes. Although these splicing-regulated are not enriched for canonical regulators viral infection, find many do replication IAV. Moreover, in several cases, specific inhibition IAV-induced pattern attenuates We further approximately quarter events regulated by hnRNP K, protein required...
Abstract Nuclear export of influenza A virus (IAV) mRNAs occurs through the nuclear pore complex (NPC). Using Auxin-Induced Degron (AID) system to rapidly degrade proteins, we show that among nucleoporins localized at nucleoplasmic side NPC, TPR is key nucleoporin required for mRNAs. recruits TR anscription and EX port (TREX)−2 NPC exporting a subset cellular By degrading components TREX-2 (GANP, Germinal-center Associated Protein; PCID2, PCI domain containing 2), require replication....