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

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

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.

Figures
Products