Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
PLoS Genet ; 10(5): e1004403, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24875882

RESUMEN

Post-translational protein modifications such as phosphorylation and ubiquitinylation are common molecular targets of conflict between viruses and their hosts. However, the role of other post-translational modifications, such as ADP-ribosylation, in host-virus interactions is less well characterized. ADP-ribosylation is carried out by proteins encoded by the PARP (also called ARTD) gene family. The majority of the 17 human PARP genes are poorly characterized. However, one PARP protein, PARP13/ZAP, has broad antiviral activity and has evolved under positive (diversifying) selection in primates. Such evolution is typical of domains that are locked in antagonistic 'arms races' with viral factors. To identify additional PARP genes that may be involved in host-virus interactions, we performed evolutionary analyses on all primate PARP genes to search for signatures of rapid evolution. Contrary to expectations that most PARP genes are involved in 'housekeeping' functions, we found that nearly one-third of PARP genes are evolving under strong recurrent positive selection. We identified a >300 amino acid disordered region of PARP4, a component of cytoplasmic vault structures, to be rapidly evolving in several mammalian lineages, suggesting this region serves as an important host-pathogen specificity interface. We also found positive selection of PARP9, 14 and 15, the only three human genes that contain both PARP domains and macrodomains. Macrodomains uniquely recognize, and in some cases can reverse, protein mono-ADP-ribosylation, and we observed strong signatures of recurrent positive selection throughout the macro-PARP macrodomains. Furthermore, PARP14 and PARP15 have undergone repeated rounds of gene birth and loss during vertebrate evolution, consistent with recurrent gene innovation. Together with previous studies that implicated several PARPs in immunity, as well as those that demonstrated a role for virally encoded macrodomains in host immune evasion, our evolutionary analyses suggest that addition, recognition and removal of ADP-ribosylation is a critical, underappreciated currency in host-virus conflicts.


Asunto(s)
Adenosina Difosfato Ribosa/metabolismo , Evolución Molecular , Inmunidad Innata/genética , Virus/patogenicidad , ADP Ribosa Transferasas/genética , ADP Ribosa Transferasas/metabolismo , Adenosina Difosfato Ribosa/genética , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Procesamiento Proteico-Postraduccional , Virus/genética
2.
PLoS Genet ; 4(1): e21, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18225958

RESUMEN

Intrinsic immunity relies on specific recognition of viral epitopes to mount a cell-autonomous defense against viral infections. Viral recognition determinants in intrinsic immunity genes are expected to evolve rapidly as host genes adapt to changing viruses, resulting in a signature of adaptive evolution. Zinc-finger antiviral protein (ZAP) from rats was discovered to be an intrinsic immunity gene that can restrict murine leukemia virus, and certain alphaviruses and filoviruses. Here, we used an approach combining molecular evolution and cellular infectivity assays to address whether ZAP also acts as a restriction factor in primates, and to pinpoint which protein domains may directly interact with the virus. We find that ZAP has evolved under positive selection throughout primate evolution. Recurrent positive selection is only found in the poly(ADP-ribose) polymerase (PARP)-like domain present in a longer human ZAP isoform. This PARP-like domain was not present in the previously identified and tested rat ZAP gene. Using infectivity assays, we found that the longer isoform of ZAP that contains the PARP-like domain is a stronger suppressor of murine leukemia virus expression and Semliki forest virus infection. Our study thus finds that human ZAP encodes a potent antiviral activity against alphaviruses. The striking congruence between our evolutionary predictions and cellular infectivity assays strongly validates such a combined approach to study intrinsic immunity genes.


Asunto(s)
Antivirales/metabolismo , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/metabolismo , Selección Genética , Infecciones por Alphavirus/virología , Secuencia de Aminoácidos , Animales , Células HeLa , Humanos , Funciones de Verosimilitud , Datos de Secuencia Molecular , Filogenia , Primates , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Estructura Terciaria de Proteína , Ratas , Virus de los Bosques Semliki , Especificidad de la Especie
3.
BMC Evol Biol ; 10: 223, 2010 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-20649995

RESUMEN

BACKGROUND: Interleukin-4 (IL4) is a secreted immunoregulatory cytokine critically involved in host protection from parasitic helminths 1. Reasoning that helminths may have evolved mechanisms to antagonize IL4 to maximize their dispersal, we explored mammalian IL4 evolution. RESULTS: This analysis revealed evidence of diversifying selection at 15 residues, clustered in epitopes responsible for IL4 binding to its Type I and Type II receptors. Such a striking signature of selective pressure suggested either recurrent episodes of pathogen antagonism or ligand/receptor co-evolution. To test the latter possibility, we performed detailed functional analysis of IL4 allotypes expressed by Mus musculus musculus and Mus musculus castaneus, which happen to differ at 5 residues (including three at positively selected sites) in and adjacent to the site 1 epitope that binds the IL4Ralpha subunit shared by the Type I and Type II IL4 receptors. We show that this intra-species variation affects the ability of IL4 neither to bind IL4 receptor alpha (IL4Ralpha) nor to signal biological responses through its Type I receptor. CONCLUSIONS: Our results - reminiscent of clustered positively selected sites revealing functionally important residues at host-virus interaction interfaces - are consistent with IL4 having evolved to avoid recurrent pathogen antagonism, while maintaining the capacity to bind and signal through its cognate receptor. This work exposes what may be a general feature of evolutionary conflicts fought by pathogen antagonists at host protein-protein interaction interfaces involved in immune signaling: the emergence of receptor-binding ligand epitopes capable of buffering amino acid variation.


Asunto(s)
Evolución Molecular , Interleucina-4/genética , Ratones/genética , Receptores de Interleucina-4/genética , Selección Genética , Secuencia de Aminoácidos , Animales , Variación Genética , Humanos , Funciones de Verosimilitud , Mamíferos/genética , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Filogenia , Unión Proteica , Estructura Secundaria de Proteína , Alineación de Secuencia , Análisis de Secuencia de ADN , Especificidad de la Especie
4.
Genetics ; 176(3): 1679-89, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17483404

RESUMEN

Mutations of pigment type switching have provided basic insight into melanocortin physiology and evolutionary adaptation. In all vertebrates that have been studied to date, two key genes, Agouti and Melanocortin 1 receptor (Mc1r), encode a ligand-receptor system that controls the switch between synthesis of red-yellow pheomelanin vs. black-brown eumelanin. However, in domestic dogs, historical studies based on pedigree and segregation analysis have suggested that the pigment type-switching system is more complicated and fundamentally different from other mammals. Using a genomewide linkage scan on a Labrador x greyhound cross segregating for black, yellow, and brindle coat colors, we demonstrate that pigment type switching is controlled by an additional gene, the K locus. Our results reveal three alleles with a dominance order of black (K(B)) > brindle (k(br)) > yellow (k(y)), whose genetic map position on dog chromosome 16 is distinct from the predicted location of other pigmentation genes. Interaction studies reveal that Mc1r is epistatic to variation at Agouti or K and that the epistatic relationship between Agouti and K depends on the alleles being tested. These findings suggest a molecular model for a new component of the melanocortin signaling pathway and reveal how coat-color patterns and pigmentary diversity have been shaped by recent selection.


Asunto(s)
Segregación Cromosómica , Epistasis Genética , Ligamiento Genético , Color del Cabello/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Receptor de Melanocortina Tipo 1/genética , Proteína de Señalización Agouti , Alelos , Animales , Mapeo Cromosómico , Cromosomas , Perros , Hormonas Estimuladoras de los Melanocitos/antagonistas & inhibidores , Pigmentación/genética
5.
Cell Host Microbe ; 4(3): 249-59, 2008 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-18779051

RESUMEN

The primate APOBEC3 gene locus encodes a family of proteins (APOBEC3A-H) with various antiviral and antiretroelement activities. Here, we trace the evolution of APOBEC3H activity in hominoids to identify a human-specific loss of APOBEC3H antiviral activity. Reconstruction of the predicted ancestral human APOBEC3H protein shows that human ancestors encoded a stable form of this protein with potent antiviral activity. Subsequently, the antiviral activity of APOBEC3H was lost via two polymorphisms that are each independently sufficient to destabilize the protein. Nonetheless, an APOBEC3H allele that encodes a stably expressed protein is still maintained at high frequency, primarily in African populations. This stable APOBEC3H protein has potent activity against retroviruses and retrotransposons, including HIV and LINE-1 elements. The surprising finding that APOBEC3H antiviral activity has been lost in the majority of humans may have important consequences for our susceptibility to retroviral infections as well as ongoing retroelement proliferation in the human genome.


Asunto(s)
Antirretrovirales/metabolismo , Citosina Desaminasa/genética , Citosina Desaminasa/metabolismo , Evolución Molecular , Secuencia de Aminoácidos , Aminohidrolasas , Animales , Población Negra/genética , Línea Celular , Citosina Desaminasa/química , Frecuencia de los Genes , VIH/fisiología , Hominidae/genética , Hominidae/metabolismo , Humanos , Elementos de Nucleótido Esparcido Largo , Datos de Secuencia Molecular , Mutación , Alineación de Secuencia , Replicación Viral
6.
Science ; 318(5855): 1418-23, 2007 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-17947548

RESUMEN

Genetic analysis of mammalian color variation has provided fundamental insight into human biology and disease. In most vertebrates, two key genes, Agouti and Melanocortin 1 receptor (Mc1r), encode a ligand-receptor system that controls pigment type-switching, but in domestic dogs, a third gene is implicated, the K locus, whose genetic characteristics predict a previously unrecognized component of the melanocortin pathway. We identify the K locus as beta-defensin 103 (CBD103) and show that its protein product binds with high affinity to the Mc1r and has a simple and strong effect on pigment type-switching in domestic dogs and transgenic mice. These results expand the functional role of beta-defensins, a protein family previously implicated in innate immunity, and identify an additional class of ligands for signaling through melanocortin receptors.


Asunto(s)
Perros/genética , Color del Cabello/genética , Receptor de Melanocortina Tipo 1/metabolismo , beta-Defensinas/genética , beta-Defensinas/metabolismo , Proteína de Señalización Agouti/genética , Proteína de Señalización Agouti/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular , Mapeo Cromosómico , Perros/metabolismo , Femenino , Haplotipos , Humanos , Queratinocitos/metabolismo , Masculino , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Mutación , Polimorfismo Genético , Análisis de Secuencia de ADN , Eliminación de Secuencia , Transducción de Señal , Piel/metabolismo , beta-Defensinas/química
7.
J Virol ; 80(8): 3853-62, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16571802

RESUMEN

The APOBEC3 genes encode cytidine deaminases that act as components of an intrinsic immune defense that have potent activity against a variety of retroelements. This family of genes has undergone a rapid expansion from one or two genes in nonprimate mammals to at least seven members in primates. Here we describe the evolution and function of an uncharacterized antiviral effector, APOBEC3H, which represents the most evolutionarily divergent APOBEC3 gene found in primates. We found that APOBEC3H has undergone significant adaptive evolution in primates. Consistent with our previous findings implicating adaptively evolving APOBEC3 genes as antiviral effectors, APOBEC3H from Old World monkeys (OWMs) has efficient antiviral activity against primate lentiviruses, is sensitive to inactivation by the simian immunodeficiency virus Vif protein, and is capable of hypermutating retroviral genomes. In contrast, human APOBEC3H is inherently poorly expressed in primate cells and is ineffective at inhibiting retroviral replication. Both OWM and human APOBEC3H proteins can be expressed in bacteria, where they display significant DNA mutator activity. Thus, humans have retained an APOBEC3H gene that encodes a functional, but poorly expressed, cytidine deaminase with no apparent antiviral activity. The consequences of the lack of antiviral activity of human APOBEC3H are likely to be relevant to the current-day abilities of humans to combat retroviral challenges.


Asunto(s)
Evolución Biológica , Citosina Desaminasa/genética , Citosina Desaminasa/fisiología , Primates/genética , Infecciones por Retroviridae/prevención & control , Desaminasas APOBEC , Animales , Citidina Desaminasa , Humanos , Macaca , Mutación , Especificidad de Órganos , ARN Mensajero/análisis , Retroviridae/genética
8.
Mamm Genome ; 16(4): 262-72, 2005 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15965787

RESUMEN

The type of pigment synthesized in mammalian hair, yellow-red pheomelanin or black-brown eumelanin, depends on the interaction between Agouti protein and the Melanocortin 1 receptor. Although the genetics of pigmentation is broadly conserved across most mammalian species, pigment type-switching in domestic dogs is unusual because a yellow-tan coat with variable amounts of dark hair is thought to be caused by an allele of the Agouti locus referred to as fawn or sable (a(y)). In a large survey covering thirty seven breeds, we identified an Agouti allele with two missense alterations, A82S and R83H, which was present (heterozygous or homozygous) in 41 dogs (22 breeds) with a fawn or sable coat, but was absent from 16 dogs (8 breeds) with a black-and-tan or tricolor phenotype. In an additional 33 dogs (14 breeds) with a eumelanic coat, 8 (German Shepherd Dogs, Groenendaels, Schipperkes, or Shetland Sheepdogs) were homozygous for a previously reported mutation, non-agouti R96C; the remainder are likely to have carried dominant black, which is independent of and epistatic to Agouti. This work resolves some of the complexity in dog coat color genetics and provides diagnostic opportunities and practical guidelines for breeders.


Asunto(s)
Alelos , Perros/genética , Cabello/fisiología , Péptidos y Proteínas de Señalización Intercelular/genética , Pigmentación/genética , Proteína de Señalización Agouti , Animales , Secuencia de Bases , Cartilla de ADN , Datos de Secuencia Molecular , Mutación/genética , Linaje , Pigmentación/fisiología , Análisis de Secuencia de ADN , Especificidad de la Especie
9.
Mamm Genome ; 15(10): 798-808, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15520882

RESUMEN

The interaction between two genes, Agouti and Melanocortin-1 receptor ( Mc1r), produces diverse pigment patterns in mammals by regulating the type, amount, and distribution pattern of the two pigment types found in mammalian hair: eumelanin (brown/black) and pheomelanin (yellow/red). In domestic dogs ( Canis familiaris), there is a tremendous variation in coat color patterns between and within breeds; however, previous studies suggest that the molecular genetics of pigment-type switching in dogs may differ from that of other mammals. Here we report the identification and characterization of the Agouti gene from domestic dogs, predicted to encode a 131-amino-acid secreted protein 98% identical to the fox homolog, and which maps to chromosome CFA24 in a region of conserved linkage. Comparative analysis of the Doberman Pinscher Agouti cDNA, the fox cDNA, and 180 kb of Doberman Pinscher genomic DNA suggests that, as with laboratory mice, different pigment-type-switching patterns in the canine family are controlled by alternative usage of different promoters and untranslated first exons. A small survey of Labrador Retrievers, Greyhounds, Australian Shepherds, and German Shepherd Dogs did not uncover any polymorphisms, but we identified a single nucleotide variant in black German Shepherd Dogs predicted to cause an Arg-to-Cys substitution at codon 96, which is likely to account for recessive inheritance of a uniform black coat.


Asunto(s)
Perros/genética , Color del Cabello/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Melaninas/metabolismo , Receptor de Melanocortina Tipo 1/genética , Pigmentación de la Piel/genética , Proteína de Señalización Agouti , Sustitución de Aminoácidos/genética , Animales , Secuencia de Bases , Cartilla de ADN/genética , Exones/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Datos de Secuencia Molecular , Regiones Promotoras Genéticas/genética , Receptor de Melanocortina Tipo 1/metabolismo , Homología de Secuencia de Aminoácido
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA