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

  • Aging Cell. 2025 Jun;24(6):e70038. doi: 10.1111/acel.70038.
Rewayd Shalash  1 ,  Dror Michael Solomon  1 ,  Mor Levi-Ferber  1 ,  Henrik von Chrzanowski  1  2 ,  Mohammad Khaled Atrash  1  3 ,  Barak Nakar  1 ,  Matan Yosef Avivi  1  4 ,  Hagit Hauschner  1 ,  Aviya Swisa  1 ,  Alicia Meléndez  2  5 ,  Yaron Shav-Tal  1  3 ,  Sivan Henis-Korenblit  1
Affiliations
  • 1. The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
  • 2. Biology Department, Queens College, City University of New York (CUNY), New York, USA.
  • 3. Institute of Nanotechnology and Advanced Materials (BINA), Bar-Ilan University, Ramat-Gan, Israel.
  • 4. The Metabolomics Unit at the Kanbar Core Facility, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
  • 5. Biology and Biochemistry PhD Programs, The Graduate Center of the City University of New York, New York, USA.
PMID: 40304211 DOI: 10.1111/acel.70038
Abstract

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.

Keywords
C. elegans; HLH‐30; TFEB; chaperones; coenzyme A; iron–sulfur clusters; pantothenate kinase; protein quality control; proteostasis.
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