Lisa N Kinch

University of Texas at Dallas, Richardson, Texas, United States

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Publications (79)731.49 Total impact

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    ABSTRACT: The type VI secretion system (T6SS) is a widespread protein secretion apparatus used by Gram-negative bacteria to deliver toxic effector proteins into adjacent bacterial or host cells. Here, we uncovered a role in interbacterial competition for the two T6SSs encoded by the marine pathogen Vibrio alginolyticus. Using comparative proteomics and genetics, we identified their effector repertoires. In addition to the previously described effector V12G01_02265, we identified three new effectors secreted by T6SS1, indicating that the T6SS1 secretes at least four antibacterial effectors, of which three are members of the MIX-effector class. We also showed that the T6SS2 secretes at least three antibacterial effectors. Our findings revealed that many MIX-effectors belonging to clan V are "orphan" effectors that neighbor mobile elements and are shared between marine bacteria via horizontal gene transfer. We demonstrated that a MIX V-effector from V. alginolyticus is a functional T6SS effector when ectopically expressed in another Vibrio species. We propose that mobile MIX V-effectors serve as an environmental reservoir of T6SS effectors that are shared and used to diversify antibacterial toxin repertoires in marine bacteria, resulting in enhanced competitive fitness.
    PLoS Pathogens 08/2015; 11(8):e1005128. DOI:10.1371/journal.ppat.1005128 · 8.06 Impact Factor
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    ABSTRACT: The existence of extracellular phosphoproteins has been acknowledged for over a century. However, research in this area has been undeveloped largely because the kinases that phosphorylate secreted proteins have escaped identification. Fam20C is a kinase that phosphorylates S-x-E/pS motifs on proteins in milk and in the extracellular matrix of bones and teeth. Here, we show that Fam20C generates the majority of the extracellular phosphoproteome. Using CRISPR/Cas9 genome editing, mass spectrometry, and biochemistry, we identify more than 100 secreted phosphoproteins as genuine Fam20C substrates. Further, we show that Fam20C exhibits broader substrate specificity than previously appreciated. Functional annotations of Fam20C substrates suggest roles for the kinase beyond biomineralization, including lipid homeostasis, wound healing, and cell migration and adhesion. Our results establish Fam20C as the major secretory pathway protein kinase and serve as a foundation for new areas of investigation into the role of secreted protein phosphorylation in human biology and disease. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 06/2015; 161(7):1619-1632. DOI:10.1016/j.cell.2015.05.028 · 33.12 Impact Factor
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    ABSTRACT: The eukaryotic protozoan parasite, Trypanosoma brucei, is the causative agent of human African trypanosomiasis (HAT)2. Polyamine biosynthesis is essential in T. brucei and the polyamine spermidine is required for synthesis of a novel cofactor called trypanothione and for deoxyhypusine modification of eukaryotic translation initiation factor 5A (eIF5A). eIF5A promotes translation of proteins containing polyprolyl tracks in mammals and yeast. To evaluate the function of eIF5A in T. brucei we used RNA interference (RNAi) to knockdown eIF5A levels and found that it is essential for T. brucei growth. The RNAi-induced growth defect was complemented by expression of wild-type human eIF5A but not by a Lys-50 mutant that blocks modification by deoxyhypusine. Bioinformatic analysis showed that 15% of the T. brucei proteome contains 3 or more consecutive prolines and that actin-related proteins and cysteine proteases were highly enriched in the group. Steady-state protein levels of representative proteins containing 9 consecutive prolines that are involved in actin assembly (formin and CAP/Srv2p) were significantly reduced by knockdown of eIF5A. Several T. brucei polyprolyl proteins are involved in flagellar assembly. Knockdown of TbeIF5A led to abnormal cell morphologies and detached flagella suggesting eIF5A is important for translation of proteins needed for these processes. Potential specialized functions for eIF5A in T. brucei in translation of variable surface glycoproteins (VSGs) were also uncovered. Inhibitors of deoxyhypusination would be expected to cause a pleomorphic effect on multiple cell processes, suggesting deoxyhypusine/hypusine biosynthesis could be a promising drug target in not just T. brucei but in other eukaryotic pathogens. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 06/2015; DOI:10.1074/jbc.M115.656785 · 4.57 Impact Factor
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    ABSTRACT: Inference of homology from protein sequences provides an essential tool for analyzing protein structure, function, and evolution. Current sequence-based homology search methods are still unable to detect many similarities evident from protein spatial structures. In computer science a search engine can be improved by considering networks of known relationships within the search database. Here, we apply this idea to protein-sequence-based homology search and show that it dramatically enhances the search accuracy. Our new method, COMPADRE (COmparison of Multiple Protein sequence Alignments using Database RElationships) assesses the relationship between the query sequence and a hit in the database by considering the similarity between the query and hit's known homologs. This approach increases detection quality, boosting the precision rate from 18% to 83% at half-coverage of all database homologs. The increased precision rate allows detection of a large fraction of protein structural relationships, thus providing structure and function predictions for previously uncharacterized proteins. Our results suggest that this general approach is applicable to a wide variety of methods for detection of biological similarities. The web server is available at prodata.swmed.edu/compadre.
    Proceedings of the National Academy of Sciences 06/2015; 112(22):7003-8. DOI:10.1073/pnas.1424324112 · 9.81 Impact Factor
  • Wenlin Li · Lisa N Kinch · P Andrew Karplus · Nick V Grishin
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    ABSTRACT: Chameleon sequences (ChSeqs) refer to sequence strings of identical amino acids that can adopt different conformations in protein structures. Researchers have detected and studied ChSeqs to understand the interplay between local and global interactions in protein structure formation. The different secondary structures adopted by one ChSeq challenge sequence-based secondary structure predictors. With increasing numbers of available PDB structures, we here identify a large set of ChSeqs ranging from 6 to 10 residues in length. The homologous ChSeqs discovered highlight the structural plasticity involved in biological function. Compared to previous studies, the set of unrelated ChSeqs found represents an about 20-fold increase in the number of detected sequences, as well as an increase in the longest ChSeq length from 8 to 10 residues. We applied secondary structure predictors on our ChSeqs and found that methods based on a sequence profile outperformed methods based on a single sequence. For the unrelated ChSeqs the evolutionary information provided by the sequence profile typically allows successful prediction of the prevailing secondary structure adopted in each protein family. Our dataset will facilitate future studies of ChSeqs, as well as interpretations of the interplay between local and non-local interactions. A user-friendly web interface for this ChSeq database is available at: prodata.swmed.edu/chseq. This article is protected by copyright. All rights reserved. © 2015 The Protein Society.
    Protein Science 05/2015; 24(7). DOI:10.1002/pro.2689 · 2.85 Impact Factor
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    ABSTRACT: Protein phosphorylation is a nearly universal post-translation modification involved in a plethora of cellular events. Even though phosphorylation of extracellular proteins had been observed, the identity of the kinases that phosphorylate secreted proteins remained a mystery until recently. Advances in genome sequencing and genetic studies have paved the way for the discovery of a new class of kinases that localize within the endoplasmic reticulum, Golgi apparatus and the extracellular space. These novel kinases phosphorylate proteins and proteoglycans in the secretory pathway and appear to regulate various extracellular processes. Mutations in these kinases cause human disease, thus underscoring the biological importance of phosphorylation within the secretory pathway. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 04/2015; DOI:10.1016/j.bbapap.2015.03.015 · 4.66 Impact Factor
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    ABSTRACT: Understanding the evolution of a protein, including both close and distant relationships, often reveals insight into its structure and function. Fast and easy access to such up-to-date information facilitates research. We have developed a hierarchical evolutionary classification of all proteins with experimentally determined spatial structures, and presented it as an interactive and updatable online database. ECOD (Evolutionary Classification of protein Domains) is distinct from other structural classifications in that it groups domains primarily by evolutionary relationships (homology), rather than topology (or "fold"). This distinction highlights cases of homology between domains of differing topology to aid in understanding of protein structure evolution. ECOD uniquely emphasizes distantly related homologs that are difficult to detect, and thus catalogs the largest number of evolutionary links among structural domain classifications. Placing distant homologs together underscores the ancestral similarities of these proteins and draws attention to the most important regions of sequence and structure, as well as conserved functional sites. ECOD also recognizes closer sequence-based relationships between protein domains. Currently, approximately 100,000 protein structures are classified in ECOD into 9,000 sequence families clustered into close to 2,000 evolutionary groups. The classification is assisted by an automated pipeline that quickly and consistently classifies weekly releases of PDB structures and allows for continual updates. This synchronization with PDB uniquely distinguishes ECOD among all protein classifications. Finally, we present several case studies of homologous proteins not recorded in other classifications, illustrating the potential of how ECOD can be used to further biological and evolutionary studies.
    PLoS Computational Biology 12/2014; 10(12):e1003926. DOI:10.1371/journal.pcbi.1003926 · 4.87 Impact Factor
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    ABSTRACT: To further understand the molecular distinctions between kidney cancer subtypes, we analyzed exome, transcriptome and copy number alteration data from 167 primary human tumors that included renal oncocytomas and non-clear cell renal cell carcinomas (nccRCCs), consisting of papillary (pRCC), chromophobe (chRCC) and translocation (tRCC) subtypes. We identified ten significantly mutated genes in pRCC, including MET, NF2, SLC5A3, PNKD and CPQ. MET mutations occurred in 15% (10/65) of pRCC samples and included previously unreported recurrent activating mutations. In chRCC, we found TP53, PTEN, FAAH2, PDHB, PDXDC1 and ZNF765 to be significantly mutated. Gene expression analysis identified a five-gene set that enabled the molecular classification of chRCC, renal oncocytoma and pRCC. Using RNA sequencing, we identified previously unreported gene fusions, including ACTG1-MITF fusion. Ectopic expression of the ACTG1-MITF fusion led to cellular transformation and induced the expression of downstream target genes. Finally, we observed upregulation of the anti-apoptotic factor BIRC7 in MiTF-high RCC tumors, suggesting a potential therapeutic role for BIRC7 inhibitors.
    Nature Genetics 11/2014; 47(1). DOI:10.1038/ng.3146 · 29.65 Impact Factor
  • Jimin Pei · Wenlin Li · Lisa N Kinch · Nick V Grishin
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    ABSTRACT: The heme-copper oxidase superfamily includes heme-copper oxidases (HCOs) in aerobic respiratory chains and nitric oxide reductases (NORs) in the denitrification pathway. The HCO/NOR catalytic subunit has a core structure consisting of 12 transmembrane helices (TMHs) arranged in three-fold rotational pseudosymmetry, with six conserved histidines for heme and metal binding. Using sensitive sequence similarity searches, we detected a number of novel HCO/NOR homologs and named them HCO Homology (HCOH) proteins. Several HCOH families possess only four TMHs that exhibit the most pronounced similarity to the last four TMHs (TMHs 9-12) of HCOs/NORs. Encoded by independent genes, four-TMH HCOH proteins represent a single evolutionary unit (EU) that relates to each of the three homologous EUs from HCO/NOR comprising TMHs 1-4, TMHs 5-8 and TMHs 9-12. Single-EU HCOH proteins could form homotrimers or heterotrimers to maintain the general structure and ligand-binding sites defined by the HCO/NOR catalytic subunit fold. The remaining HCOH families, including NnrS, have 12-TMHs and three EUs. Most three-EU HCOH proteins possess two conserved histidines and could bind a single heme. Limited experimental studies and genomic context analysis suggest that many HCOH proteins could function in the denitrification pathway and in detoxification of reactive molecules such as nitric oxide. HCO/NOR catalytic subunits exhibit remarkable structural similarity to the homotrimers of MAPEG (membrane-associated proteins in eicosanoid and glutathione metabolism) proteins. Gene duplication, fusion and fission likely play important roles in the evolution of HCOs/NORs and HCOH proteins.
    Protein Science 09/2014; 23(9). DOI:10.1002/pro.2503 · 2.85 Impact Factor
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    ABSTRACT: Vibrio parahaemolyticus is a Gram-negative halophilic bacterium and one of the leading causes of food-borne gastroenteritis. Its genome harbors two Type III Secretion Systems (T3SS1 and T3SS2), but only T3SS2 is required for enterotoxicity seen in animal models. Effector proteins secreted from T3SS2 have been previously shown to promote colonization of the intestinal epithelium, invasion of host cells, and destruction of the epithelial monolayer. In this study, we identify VPA1380, a T3SS2 effector protein that is toxic when expressed in yeast. Bioinformatic analyses revealed that VPA1380 is highly similar to the inositol hexakisphosphate (IP6)-inducible cysteine protease domains of several large bacterial toxins. Mutations in conserved catalytic residues and residues in the putative IP6-binding pocket abolished toxicity in yeast. Furthermore, VPA1380 was not toxic in IP6 deficient yeast cells. Therefore, our findings suggest that VPA1380 is a cysteine protease that requires IP6 as an activator.
    PLoS ONE 08/2014; 9(8)(8):e104387. DOI:10.1371/journal.pone.0104387 · 3.23 Impact Factor
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    ABSTRACT: Bacteria use diverse mechanisms to kill, manipulate, and compete with other cells. The recently discovered type VI secretion system (T6SS) is widespread in bacterial pathogens and used to deliver virulence effector proteins into target cells. Using comparative proteomics, we identified two previously unidentified T6SS effectors that contained a conserved motif. Bioinformatic analyses revealed that this N-terminal motif, named MIX (marker for type six effectors), is found in numerous polymorphic bacterial proteins that are primarily located in the T6SS genome neighborhood. We demonstrate that several MIX-containing proteins are T6SS effectors and that they are not required for T6SS activity. Thus, we propose that MIX-containing proteins are T6SS effectors. Our findings allow for the identification of numerous uncharacterized T6SS effectors that will undoubtedly lead to the discovery of new biological mechanisms.
    Proceedings of the National Academy of Sciences 06/2014; 111(25). DOI:10.1073/pnas.1406110111 · 9.81 Impact Factor
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    ABSTRACT: Bacterial Type III Secretion Systems deliver effectors into host cells to manipulate cellular processes to the advantage of the pathogen. Many host targets of these effectors are found on membranes. Therefore, to identify their targets, effectors often use specialized membrane-localization domains to localize to appropriate host membranes. However, the molecular mechanisms used by many domains are unknown. Here we identify a conserved bacterial phosphoinositide-binding domain (BPD) that is found in functionally diverse Type III effectors of both plant and animal pathogens. We show that members of the BPD family functionally bind phosphoinositides and mediate localization to host membranes. Moreover, NMR studies reveal that the BPD of the newly identified Vibrio parahaemolyticus Type III effector VopR is unfolded in solution, but folds into a specific structure upon binding its ligand phosphatidylinositol-(4,5)-bisphosphate. Thus, our findings suggest a possible mechanism for promoting refolding of Type III effectors after delivery into host cells.
    Nature Communications 12/2013; 4:2973. DOI:10.1038/ncomms3973 · 10.74 Impact Factor
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    ABSTRACT: Tuberculosis, caused by Mycobacterium tuberculosis, remains a devastating human infectious disease, causing two million deaths annually. We previously demonstrated that M. tuberculosis induces an enzyme, heme oxygenase (HO1), that produces carbon monoxide (CO) gas and that M. tuberculosis adapts its transcriptome during CO exposure. We now demonstrate that M. tuberculosis carries a novel resistance gene to combat CO toxicity. We screened an M. tuberculosis transposon library for CO-susceptible mutants and found that disruption of Rv1829 (carbon monoxide resistance, Cor) leads to marked CO sensitivity. Heterologous expression of Cor in Escherichia coli rescued it from CO toxicity. Importantly, the virulence of the cor mutant is attenuated in a mouse model of tuberculosis. Thus, Cor is necessary and sufficient to protect bacteria from host-derived CO. Taken together, this represents the first report of a role for HO1-derived CO in controlling infection of an intracellular pathogen and the first identification of a CO resistance gene in a pathogenic organism.
    mBio 10/2013; 4(6). DOI:10.1128/mBio.00721-13 · 6.88 Impact Factor
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    ABSTRACT: Cell surface growth factor receptors couple environmental cues to the regulation of cytoplasmic homeostatic processes, including autophagy, and aberrant activation of such receptors is a common feature of human malignancies. Here, we defined the molecular basis by which the epidermal growth factor receptor (EGFR) tyrosine kinase regulates autophagy. Active EGFR binds the autophagy protein Beclin 1, leading to its multisite tyrosine phosphorylation, enhanced binding to inhibitors, and decreased Beclin 1-associated VPS34 kinase activity. EGFR tyrosine kinase inhibitor (TKI) therapy disrupts Beclin 1 tyrosine phosphorylation and binding to its inhibitors and restores autophagy in non-small-cell lung carcinoma (NSCLC) cells with a TKI-sensitive EGFR mutation. In NSCLC tumor xenografts, the expression of a tyrosine phosphomimetic Beclin 1 mutant leads to reduced autophagy, enhanced tumor growth, tumor dedifferentiation, and resistance to TKI therapy. Thus, oncogenic receptor tyrosine kinases directly regulate the core autophagy machinery, which may contribute to tumor progression and chemoresistance.
    Cell 09/2013; 154(6):1269-84. DOI:10.1016/j.cell.2013.08.015 · 33.12 Impact Factor
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    ABSTRACT: The molecular mechanism of autophagy and its relationship to other lysosomal degradation pathways remain incompletely understood. Here, we identified a previously uncharacterized mammalian-specific protein, Beclin 2, which, like Beclin 1, functions in autophagy and interacts with class III PI3K complex components and Bcl-2. However, Beclin 2, but not Beclin 1, functions in an additional lysosomal degradation pathway. Beclin 2 is required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) through its interaction with GASP1. Beclin 2 homozygous knockout mice have decreased embryonic viability, and heterozygous knockout mice have defective autophagy, increased levels of brain cannabinoid 1 receptor, elevated food intake, and obesity and insulin resistance. Our findings identify Beclin 2 as a converging regulator of autophagy and GPCR turnover and highlight the functional and mechanistic diversity of Beclin family members in autophagy, endolysosomal trafficking, and metabolism.
    Cell 08/2013; 154(5). DOI:10.1016/j.cell.2013.07.035 · 33.12 Impact Factor
  • Wenlin Li · Lisa N Kinch · Nick V Grishin
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    ABSTRACT: One approach to infer functions of new proteins from their homologs utilizes visualization of an all-against-all pairwise similarity network (A2ApsN) that exploits the speed of BLAST and avoids the complexity of multiple sequence alignment. However, identifying functions of the protein clusters in A2ApsN is never trivial, due to a lack of linking characterized proteins to their relevant information in current software packages. Given the database errors introduced by automatic annotation transfer, functional deduction should be made from proteins with experimental studies, i.e. "reference proteins". Here, we present a web server, termed Pclust, which provides a user-friendly interface to visualize the A2ApsN, placing emphasis on such "reference proteins" and providing access to their full information in source databases, e.g. articles in PubMed. The identification of "reference proteins" and the ease of cross-database linkage will facilitate understanding the functions of protein clusters in the network, thus promoting interpretation of proteins of interest. The Pclust server is freely available at http://prodata.swmed.edu/pclust CONTACT: wenlin.li@utsouthwestern.edu; grishin@chop.swmed.edu.
    Bioinformatics 08/2013; 29(20). DOI:10.1093/bioinformatics/btt451 · 4.62 Impact Factor
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    ABSTRACT: VEGF and PDGF receptors are implicated in development and tumorigenesis and dual inhibitors like sunitinib are prescribed for cancer treatment. While mammalian VEGF and PDGF receptors are present in multiple isoforms and heterodimers, Drosophila encodes one ancestral PDGF/VEGF receptor, PVR. We identified PVR in an unbiased cell-based RNAi screen of all Drosophila kinases and phosphatases for novel regulators of TORC1. PVR is essential to sustain TORC1 and ERK activity in cultured insect cells and for maximal stimulation by insulin. CG32406 (hereafter PVRAP, for PVR adaptor protein), an SH2-domain containing protein, binds PVR and is required for TORC1 activation. TORC1 activation by PVR involves Tsc1/Tsc2 and, in a cell type-dependent manner, Lobe|PRAS40. PVR is required for cell survival in vitro, and both PVR and TORC1 are necessary for hemocyte expansion in vivo. Constitutive PVR activation induces tumor-like structures that exhibit high TORC1 activity. Like its mammalian orthologs, PVR is inhibited by sunitinib, and sunitinib treatment phenocopies PVR loss in hemocytes. Sunitinib inhibits TORC1 in insect cells, and sunitinib-mediated TORC1 inhibition requires an intact Tsc1/Tsc2 complex. Sunitinib similarly inhibited TORC1 in human endothelial cells in a Tsc1/Tsc2-dependent manner. Our findings provide insight into the mechanism of action of PVR and may have implications for understanding sunitinib sensitivity and resistance in tumors.
    Molecular and Cellular Biology 07/2013; 33(19). DOI:10.1128/MCB.01570-12 · 5.04 Impact Factor
  • Lisa N Kinch · Nick V Grishin
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    ABSTRACT: Endopeptidase classification based on catalytic mechanism and evolutionary history has proven to be invaluable to the study of proteolytic enzymes. Such general mechanistic- and evolutionary- based groupings have launched experimental investigations, because knowledge gained for one family member tends to apply to the other closely related enzymes. The serine endopeptidases represent one of the most abundant and diverse groups, with their apparently successful proteolytic mechanism having arisen independently many times throughout evolution, giving rise to the well-studied soluble chemotrypsins and subtilisins, among many others. A large and diverse family of polytopic transmembrane proteins known as rhomboids has also evolved the serine protease mechanism. While the spatial structure, mechanism, and biochemical function of this family as intramembrane proteases has been established, the cellular roles of these enzymes as well as their natural substrates remain largely undetermined. While the evolutionary history of rhomboid proteases has been debated, sorting out the relationships among current day representatives should provide a solid basis for narrowing the knowledge gap between their biochemical and cellular functions. Indeed, some functional characteristics of rhomboid proteases can be gleaned from their evolutionary relationships. Finally, a specific case where phylogenetic profile analysis has identified proteins that contain a C-terminal processing motif (GlyGly-Cterm) as co-occurring with a set of bacterial rhomboid proteases provides an example of potential target identification through bioinformatics. This article is part of a Special Issue entitled: Intramembrane Proteases.
    Biochimica et Biophysica Acta 07/2013; 1828(12). DOI:10.1016/j.bbamem.2013.06.031 · 4.66 Impact Factor
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    ABSTRACT: Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including VHL, which is also mutated in sporadic RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BAP1 gene is mutated in sporadic RCC. BAP1, which encodes a nuclear deubiquitinase, is a two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade ccRCC and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, we sequenced the BAP1 gene in 83 unrelated probands with unexplained familial RCC. We identified a novel variant (c.41T>A; p.L14H), which cosegregated with the RCC phenotype. The p.L14H variant targets a highly conserved residue in the catalytic domain, a domain frequently targeted by missense mutations. The family with the BAP1 variant was characterized by early-onset clear cell RCC, occasionally of high Fuhrman grade, and lacked other features that characterize von Hippel-Lindau syndrome. These findings suggest that BAP1 is a familial RCC predisposing gene.
    Molecular Cancer Research 05/2013; 11(9). DOI:10.1158/1541-7786.MCR-13-0111 · 4.50 Impact Factor
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    ABSTRACT: The lysosomal degradation pathway of autophagy has a crucial role in defence against infection, neurodegenerative disorders, cancer and ageing. Accordingly, agents that induce autophagy may have broad therapeutic applications. One approach to developing such agents is to exploit autophagy manipulation strategies used by microbial virulence factors. Here we show that a peptide, Tat–beclin 1—derived from a region of the autophagy protein, beclin 1, which binds human immunodeficiency virus (HIV)-1 Nef—is a potent inducer of autophagy, and interacts with a newly identified negative regulator of autophagy, GAPR-1 (also called GLIPR2). Tat–beclin 1 decreases the accumulation of polyglutamine expansion protein aggregates and the replication of several pathogens (including HIV-1) in vitro, and reduces mortality in mice infected with chikungunya or West Nile virus. Thus, through the characterization of a domain of beclin 1 that interacts with HIV-1 Nef, we have developed an autophagy-inducing peptide that has potential efficacy in the treatment of human diseases. Autophagy functions in metazoans in cellular and tissue homeostasis, physiology, development, and protection against disease, and abnor-malities in autophagy may contribute to many different pathophysio-logical conditions 1,2 . Thus, strategies that augment autophagy may prevent or treat human disease 3 . Although some drugs in clinical use are capable of augmenting autophagy, these compounds exert pleiotropic effects, revealing an unmet need to develop specific indu-cers of autophagy. We sought to develop a specific autophagy-inducing agent with a potentially wide range of therapeutic effects. As viruses often provide key insights into the functionally important domains of host proteins, we investigated the molecular determinants governing the interaction between beclin 1, an essential autophagy protein in the class III phos-phatidylinositol-3-OH kinase (PI(3)K) complex involved in auto-phagic vesicle nucleation 4 , and the HIV-1 virulence factor, Nef 5 . These investigations led us to identify a Nef-interacting sequence of beclin 1 that is necessary and sufficient for autophagy induction and which provided the basis for the development of an autophagy-indu-cing peptide drug that has benefits in the clearance of polyglutamine expansion protein aggregates and the treatment of infectious diseases.

Publication Stats

3k Citations
731.49 Total Impact Points

Institutions

  • 2012–2015
    • University of Texas at Dallas
      Richardson, Texas, United States
  • 1994–2015
    • University of Texas Southwestern Medical Center
      • • Department of Biochemistry
      • • Department of Molecular Biology
      • • Department of Internal Medicine
      • • Department of Pharmacology
      Dallas, Texas, United States
  • 2004–2014
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States