HLH-30/TFEB Rewires the Chaperone Network to Promote Proteostasis Upon Perturbations to the Coenzyme A and Iron–Sulfur Cluster Biosynthesis Pathways

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, inhibition of the first and rate-limiting step in CoA biosynthesis can be beneficial and promote proteostasis. Impairment of the cytosolic iron–sulfur cluster formation pathway, which depends on Coenzyme A, similarly promotes proteostasis and acts in the same pathway. Proteostasis improvement by interference with the Coenzyme A/iron–sulfur cluster biosynthesis pathways is 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, which 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.