HLH-30/TFEB rewires the chaperone network to promote proteostasis under conditions of Coenzyme A and Iron-Sulfur Cluster Deficiency.

The maintenance of a properly folded proteome is critical for cellular function and organismal health, and its age-dependent collapse is associated with a wide range of diseases. Here, we find that despite the central role of Coenzyme A as a molecular cofactor in hundreds of cellular reactions, limiting Coenzyme A levels in C. elegans and in human cells, by inhibiting the conserved pantothenate kinase, promotes proteostasis. Impairment of the cytosolic iron-sulfur clusters formation pathway, which depends on Coenzyme A, similarly promotes proteostasis and acts in the same pathway. Proteostasis improvement by Coenzyme A/iron-sulfur cluster deficiencies are dependent on the conserved HLH-30/TFEB transcription factor. Strikingly, under these conditions, HLH-30 promotes proteostasis by potentiating the expression of select chaperone genes providing a chaperone-mediated proteostasis shield, rather than by its established role as an autophagy and lysosome biogenesis promoting factor. This reflects the versatile nature of this conserved transcription factor, that can transcriptionally activate a wide range of protein quality control mechanisms, including chaperones and stress response genes alongside autophagy and lysosome biogenesis genes. These results highlight TFEB as a key proteostasis-promoting transcription factor and underscore it and its upstream regulators as potential therapeutic targets in proteostasis-related diseases.

Identification of healthspan-promoting genes in Caenorhabditis elegans based on a human GWAS study.

To find drivers of healthy ageing, a genome-wide association study (GWAS) was performed in healthy and unhealthy older individuals. Healthy individuals were defined as free from cardiovascular disease, stroke, heart failure, major adverse cardiovascular event, diabetes, dementia, cancer, chronic obstructive pulmonary disease (COPD), asthma, rheumatism, Crohn's disease, malabsorption or kidney disease. Six single nucleotide polymorphisms (SNPs) with unknown function associated with ten human genes were identified as candidate healthspan markers. Thirteen homologous or closely related genes were selected in the model organism C. elegans for evaluating healthspan after targeted RNAi-mediated knockdown using pathogen resistance, muscle integrity, chemotaxis index and the activity of known longevity and stress response pathways as healthspan reporters. In addition, lifespan was monitored in the RNAi-treated nematodes. RNAi knockdown of yap-1, wwp-1, paxt-1 and several acdh genes resulted in heterogeneous phenotypes regarding muscle integrity, pathogen resistance, chemotactic behaviour, and lifespan. Based on these observations, we hypothesize that their human homologues WWC2, CDKN2AIP and ACADS may play a role in health maintenance in the elderly.

Presence or absence? Primary structure, regioselectivity and evolution of Δ12/ω3 fatty acid desaturases in nematodes.

For vertebrates, the adequate supply of polyunsaturated fatty acids (PUFA) by the diet, in particular ω3 long-chain PUFA, is considered essential for neural development, growth and reproduction. In contrast to aquatic ecosystems, ω3 long-chain PUFA apparently are not widely available in the terrestrial food chain. Their de novo synthesis requires the presence of Δ12 and ω3 fatty acid desaturase enzymes, which are absent in vertebrates but present, for example, in the nematode Caenorhabditis elegans (FAT-2 and FAT-1). This raises the question if soil-dwelling nematodes offer substantial supply of these valuable nutritional compounds in terrestrial food webs. BLAST searches in available nematode genomes revealed the existence of fat-2 like genes in almost all clade III-V species, but failed to identify orthologs in clade I-II nematodes. An additional RT-PCR screen across soil-dwelling nematode species identified six novel fat-2 like genes. Hints for the genetic basis of a ω3 (fat-1) desaturase activity was found only in selected clade IV-V species, but not in clades I to III nematodes. Fatty acid pattern analyses following a PUFA-free cultivation and enzymatic characterization of six selected fat-2 or fat-1 like desaturases in yeast confirmed the findings from the genetic approaches. Thus, in similar soil habitats, taxa exist that can synthesize ω3 long-chain PUFA (as Panagrolaimus, Mesorhabditis and Caenorhabditis) whereas others are unable to do so (Acrobeloides, Cephalobus and Oscheius). While these nematodes do not differ in trophic position or major diet, distinction in reproduction mode may have led to the observed variations in desaturase genes.