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Papel da acetilação N-terminal na fertilidade e no envelhecimento
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Abstract(s)
A acetilação do N-terminal das proteínas tem um papel crucial em diferentes eventos celulares e moleculares, sendo umas das modificações proteicas mais abundantes em células eucariotas. As acetitltranferases N-terminal (NATs) são constituídas por uma subunidade catalítica e em alguns casos por uma ou mais unidades reguladoras possuindo, portanto, características individuais e atuando num conjunto de substratos específicos. A acetilação do N-terminal pode influenciar a função e a localização proteicas de diferentes formas, podendo afetar o normal desenvolvimento de organismos e a progressão tumoral.
Este trabalho tem por objetivo caracterizar a função do complexo NatC (Naa30) em Drosophila melanogaster. Naa30 é necessário para a longevidade e a perda de motilidade com a idade de moscas adultas. Naa30 é também necessário para a fertilidade dos machos uma vez que é essencial à copulação. A perda da função de Naa30 está associado a um aumento de agregados de proteínas poli-ubiquitinadas nos músculos, o que sugere que os fenótipos observados estão associados a defeitos de proteostase. No entanto, como em moscas velhas, o grau de perda de motilidade não está associado a níveis mais elevados de agregados, esta acumulação não é provavelmente causal para os fenótipos observados. Apesar das mitocôndrias serem aparentemente morfologicamente normais foi igualmente observado uma redução dos níveis de ATP em mutantes de Naa30. Concluímos então que a redução de longevidade, fertilidade e motilidade em mutantes de Naa30 estão potencialmente relacionados com defeitos de proteostase e uma redução dos níveis celulares de ATP.
Em linhas celulares humanas, NatF (Naa60) é importante para a modificação de proteínas transmembranares e para a integridade do Golgi. Uma vez que a função desta NAT em organismos multicelulares é pouco conhecida, um outro objetivo deste trabalho foi fazer uma caracterização fenotípica de um mutante do gene Naa60. Observou-se que em Drosophila, Naa60 não é essencial para a viabilidade de moscas adultas, nem para a fertilidade dos machos. Apesar da deleção desta NAT estar associada a uma ligeira redução da fertilidade das fêmeas, não foram detetados fenótipos óbvios durante a oogénese e os estádios iniciais de desenvolvimento do embrião.
N-terminal acetylation of proteins plays a crucial role in different cellular and molecular events, being one of the most abundant protein modifications in eukaryotic cells. N-terminal acetityltransferases (NATs) are made up of a catalytic subunit and in some cases one or more regulatory units having therefore individual characteristics and acting on a set of specific substrates. N-terminal acetylation may influence protein function and localization in different ways and may affect normal organism development and tumour progression. One of the aims of this work was to characterize the function of NatC (Naa30) in Drosophila melanogaster. Naa30 is required for the longevity and age-dependent motility of adult flies. Naa30 is also required for male fertility as it is essential for copulation. The loss of Naa30 function is associated with an increase in polyubiquitinated protein like-aggregates in the muscles, suggesting that the observed phenotypes result due to proteostasis defects. However, as the degree of motility loss is not associated with higher levels of polyubiquitinated protein like-aggregates, their accumulation is probably not causal for the observed phenotypes. Although the mitochondria were morphological normal, a reduction in ATP levels was observed in Naa30 mutants. We conclude that the reduction in longevity, fertility and motility in Naa30 mutants are potentially related to proteostasis defects and a reduction in cellular ATP levels. NatF (Naa60) has been previously described in human cell lines as being important for transmembrane protein modification and Golgi integrity. Since the role of this NAT during the development of multicellular organisms is poorly described, another aim of this work was to make a phenotypic characterization of a Naa60 deletion mutant. It was observed that in Drosophila, Naa60 is not essential for the viability of adult flies, nor for male fertility. Although deletion of this NAT is associated with a slight reduction in female fertility, no obvious phenotypes were detected during oogenesis and early stages of embryo development.
N-terminal acetylation of proteins plays a crucial role in different cellular and molecular events, being one of the most abundant protein modifications in eukaryotic cells. N-terminal acetityltransferases (NATs) are made up of a catalytic subunit and in some cases one or more regulatory units having therefore individual characteristics and acting on a set of specific substrates. N-terminal acetylation may influence protein function and localization in different ways and may affect normal organism development and tumour progression. One of the aims of this work was to characterize the function of NatC (Naa30) in Drosophila melanogaster. Naa30 is required for the longevity and age-dependent motility of adult flies. Naa30 is also required for male fertility as it is essential for copulation. The loss of Naa30 function is associated with an increase in polyubiquitinated protein like-aggregates in the muscles, suggesting that the observed phenotypes result due to proteostasis defects. However, as the degree of motility loss is not associated with higher levels of polyubiquitinated protein like-aggregates, their accumulation is probably not causal for the observed phenotypes. Although the mitochondria were morphological normal, a reduction in ATP levels was observed in Naa30 mutants. We conclude that the reduction in longevity, fertility and motility in Naa30 mutants are potentially related to proteostasis defects and a reduction in cellular ATP levels. NatF (Naa60) has been previously described in human cell lines as being important for transmembrane protein modification and Golgi integrity. Since the role of this NAT during the development of multicellular organisms is poorly described, another aim of this work was to make a phenotypic characterization of a Naa60 deletion mutant. It was observed that in Drosophila, Naa60 is not essential for the viability of adult flies, nor for male fertility. Although deletion of this NAT is associated with a slight reduction in female fertility, no obvious phenotypes were detected during oogenesis and early stages of embryo development.
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Keywords
Fertilidade Envelhecimento Acetilação N-terminal NATs NatC NatF