Hormetic heat shock activates HLH-30/TFEB independently of canonical nutrient-sensing pathways
- 1Center for Cardiovascular and Muscular Diseases, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Abstract
In Caenorhabditis elegans, a brief, sublethal heat shock (HS) induces a hormetic response that increases resistance to subsequent stress and extends lifespan. These benefits require hlh-30, the ortholog of mammalian transcription factor EB (TFEB). Although HS induces robust HLH-30 nuclear translocation, how this response is regulated remains poorly understood. Nutrient- and energy-sensing pathways, including mTORC1 and AMPK, regulate HLH-30/TFEB subcellular localization under other physiological conditions, but whether they mediate its nuclear translocation during HS is unknown. Here, we show that, although HS inhibited mTORC1 and dephosphorylated its conserved HLH-30 S201 target site, HLH-30 S201 phosphorylation was dispensable for HS-induced HLH-30 nuclear localization and hormetic protection. Moreover, HS remained protective in hlh-30 mutants when mTORC1 activity was reduced, revealing an HLH-30-independent component of the hormetic response. HS also activated AMPK and aak-2 was required for hormetic protection but dispensable for HS-induced HLH-30 nuclear localization and autophagosome formation. Together, these findings demonstrate that although HS engages canonical mTORC1 and AMPK signaling, these pathways do not account for HS-induced HLH-30 nuclear localization and instead make distinct contributions to hormetic protection. Our findings reveal stress-specific regulation of HLH-30/TFEB and point to additional mechanisms that drive its activation during heat stress.
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BibTeX
@misc{moreno2026hormetic,
title = {{Hormetic heat shock activates HLH-30/TFEB independently of canonical nutrient-sensing pathways}},
author = {T. M. Moreno and M. E. Brown and C. M. Lange and G. C. McLaren and D. A. Hernandez-Urbina and C.-J. Kuo and C. Kumsta},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.748694},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748694v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Hormetic heat shock activates HLH-30/TFEB independently of canonical nutrient-sensing pathways
AU - T. M. Moreno
AU - M. E. Brown
AU - C. M. Lange
AU - G. C. McLaren
AU - D. A. Hernandez-Urbina
AU - C.-J. Kuo
AU - C. Kumsta
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.748694
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.748694v1
AB - In Caenorhabditis elegans, a brief, sublethal heat shock (HS) induces a hormetic response that increases resistance to subsequent stress and extends lifespan. These benefits require hlh-30, the ortholog of mammalian transcription factor EB (TFEB). Although HS induces robust HLH-30 nuclear translocation, how this response is regulated remains poorly understood. Nutrient- and energy-sensing pathways, including mTORC1 and AMPK, regulate HLH-30/TFEB subcellular localization under other physiological conditions, but whether they mediate its nuclear translocation during HS is unknown. Here, we show that, although HS inhibited mTORC1 and dephosphorylated its conserved HLH-30 S201 target site, HLH-30 S201 phosphorylation was dispensable for HS-induced HLH-30 nuclear localization and hormetic protection. Moreover, HS remained protective in hlh-30 mutants when mTORC1 activity was reduced, revealing an HLH-30-independent component of the hormetic response. HS also activated AMPK and aak-2 was required for hormetic protection but dispensable for HS-induced HLH-30 nuclear localization and autophagosome formation. Together, these findings demonstrate that although HS engages canonical mTORC1 and AMPK signaling, these pathways do not account for HS-induced HLH-30 nuclear localization and instead make distinct contributions to hormetic protection. Our findings reveal stress-specific regulation of HLH-30/TFEB and point to additional mechanisms that drive its activation during heat stress.
ER -