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Chaperone-Mediated Autophagy (CMA) is a selective mechanism for the degradation of soluble proteins in lysosomes. To date, CMA is presumed to be restricted to mammals and birds, due the absence of an identifiable LAMP2A, a limiting and essential protein for CMA, in phylogenetically earlier species. However, we recently identified in several fish species contigs displaying high homology with the mammalian lamp2a, suggesting that CMA appeared much earlier during evolution than initially thought.

General objective of the project and the main issues raised

In this project, we propose to define for the first time whether or not a CMA process is ancestral to mammalian/bird species and determine the physiological relevance of the newly identified lamp2a homolog in fish. To address this issue, our strategy is based on two complementary approaches. A first task aims to characterize the repertoire and the expression of genes involved in CMA in a large number of fish species. The growing number of fish species whose genome was completely sequenced as well as our advances in transcriptome analysis allows including in our study a large number of fish species and thus to provide a comprehensive picture of the “genetic structure” of CMA in fish. A second task seeks to decipher the physiological role of the newly identified lamp2a homolog in fish. Recently, we have generated knockout medaka (Oryzias latipes) for the corresponding lamp2a splice variant of the lamp2 gene, by using the genome-editing tool CRISPR-Cas9. We have therefore planned to perform an exhaustive phenotyping of the lamp2a mutant medaka (at both histological, biochemical and molecular levels) in order to determine the metabolic changes induced by the deletion of lamp2a and the possible existence of a CMA activity in medaka.

Duration: Beginning of project on 15/01/2018 for 36 months