Chaperone-Mediated Autophagy in the Light of Evolution: Insight from Fish

Abstract

Chaperone-mediated autophagy (CMA) is a major pathway of lysosomal proteolysis recognized as a key player of the control of numerous cellular functions, and whose defects have been associated with several human pathologies. To date, this cellular function is presumed to be restricted to mammals and birds, due to the absence of an identifiable lysosome-associated membrane protein 2A (LAMP2A), a limiting and essential protein for CMA, in nontetrapod species. However, the recent identification of expressed sequences displaying high homology with mammalian LAMP2A in several fish species challenges that view and suggests that CMA likely appeared earlier during evolution than initially thought. In the present study, we provide a comprehensive picture of the evolutionary history of the LAMP2 gene in vertebrates and demonstrate that LAMP2 indeed appeared at the root of the vertebrate lineage. Using a fibroblast cell line from medaka fish (Oryzias latipes), we further show that the splice variant lamp2a controls, upon long-term starvation, the lysosomal accumulation of a fluorescent reporter commonly used to track CMA in mammalian cells. Finally, to address the physiological role of Lamp2a in fish, we generated knockout medaka for that specific splice variant, and found that these deficient fish exhibit severe alterations in carbohydrate and fat metabolisms, in consistency with existing data in mice deficient for CMA in liver. Altogether, our data provide the first evidence for a CMA-like pathway in fish and bring new perspectives on the use of complementary genetic models, such as zebrafish or medaka, for studying CMA in an evolutionary perspective.

Genistein Induces Adipogenic and Autophagic Effects in Rainbow Trout (Oncorhynchus mykiss) Adipose Tissue: In Vitro and In Vivo Models

“…Until recently, the CMA process was thought to be restricted to mammals and birds [ 78 ], and, for this reason, it was not initially considered for the present study. However, a very recent work by Lescat and co-workers has shown that CMA also exists in fish [ 79 ], which opens new questions for future studies. Altogether, these data are in accordance with a previous study by Cleveland [ 23 ], which reported increased gene expression of multiple autophagy-related genes (e.g., atg4b , lc3b , gabarapl1 , ctsd ) in day 7 primary myocytes from rainbow trout exposed to a high dose of GE (100 μM).…”

Lamp1 mediates lipid transport, but is dispensable for autophagy inDrosophila

“…In contrast to the two partially redundant mouse Lamp1/2 genes, the Drosophila melanogaster genome contains a single annotated Lamp1 gene evolutionarily related to vertebrate LAMP1/2 that remains uncharacterized [32,33]. To our surprise, we find that Drosophila Lamp1 null mutants are homozygous viable and show no delay during development, suggesting normal steroid hormone signaling.…”

Regulation of heat shock proteins 70 and their role in plant immunity

“…Chaperone-mediated autophagy is mediated by cytosolic HSP70s and targets proteins containing the signal motif KFERQ ( Fernández-Fernández et al , 2017 ). This was the first described chaperone-assisted pathway but requires a receptor that seems to be missing in plant lineages ( Lescat et al , 2020 ). Similarly, the autophagy pathway mediated by endoplasmic HSP70 has not yet been confirmed in plants ( Cha-Molstad et al , 2015 ).…”