RESUMEN
Selective autophagy is a catabolic process with which cellular material is specifically targeted for degradation by lysosomes. The function of selective autophagic degradation of self-components in the regulation of innate immunity is still unclear. Here we show that Drosophila Kenny, the homolog of mammalian IKKγ, is a selective autophagy receptor that mediates the degradation of the IκB kinase complex. Selective autophagic degradation of the IκB kinase complex prevents constitutive activation of the immune deficiency pathway in response to commensal microbiota. We show that autophagy-deficient flies have a systemic innate immune response that promotes a hyperplasia phenotype in the midgut. Remarkably, human IKKγ does not interact with mammalian Atg8-family proteins. Using a mathematical model, we suggest mechanisms by which pathogen selection might have driven the loss of LIR motif functionality during evolution. Our results suggest that there may have been an autophagy-related switch during the evolution of the IKKγ proteins in metazoans.
Asunto(s)
Autofagia/genética , Proteínas de Drosophila/genética , Quinasa I-kappa B/genética , Inmunidad Innata/genética , Microbiota/inmunología , Simbiosis/inmunología , Animales , Animales Modificados Genéticamente , Autofagia/inmunología , Familia de las Proteínas 8 Relacionadas con la Autofagia/metabolismo , Drosophila , Proteínas de Drosophila/inmunología , Células HeLa , Humanos , Hiperplasia/genética , Quinasa I-kappa B/inmunología , Quinasa I-kappa B/metabolismo , Inmunidad Innata/inmunología , Infecciones/inmunología , Intestinos/patología , Modelos Teóricos , FenotipoRESUMEN
The discovery of evolutionarily conserved Atg genes required for autophagy in yeast truly revolutionized this research field and made it possible to carry out functional studies on model organisms. Insects including Drosophila are classical and still popular models to study autophagy, starting from the 1960s. This review aims to summarize past achievements and our current knowledge about the role and regulation of autophagy in Drosophila, with an outlook to yeast and mammals. The basic mechanisms of autophagy in fruit fly cells appear to be quite similar to other eukaryotes, and the role that this lysosomal self-degradation process plays in Drosophila models of various diseases already made it possible to recognize certain aspects of human pathologies. Future studies in this complete animal hold great promise for the better understanding of such processes and may also help finding new research avenues for the treatment of disorders with misregulated autophagy.