2. Academic Validation
  3. The non-canonical Smoothened-AMPK axis regulates Smaug1 biomolecular condensates

The non-canonical Smoothened-AMPK axis regulates Smaug1 biomolecular condensates

  • J Cell Sci. 2025 Feb 10:jcs.263433. doi: 10.1242/jcs.263433.
María Gabriela Thomas 1 2,  Ana Julia Fernández-Alvarez 1 2,  Macarena Giménez 1 3,  Francisco Corvetto Aristarain 1 3,  Lucas Helio Cozza 1 2 3,  Jerónimo Pimentel 1 2 3,  João Pessoa 4,  Malena Lucía Pascual 1 2 3,  Lara Boscaglia 1,  Martín Habif 5 6,  Agustín Corbat 5 6,  Pablo Ezequiel La Spina 1 2 3,  Tomás Peters 1 2 3,  Diego Martín Bustos 7 8,  Maria Carmo-Fonseca,  Hernán Edgardo Grecco 5 6,  Graciela Lidia Boccaccio 1 2 3
Affiliations

Affiliations

  • 1 Fundación Instituto Leloir (FIL), Av Patricias Argentinas 435, C1405BWE Buenos Aires, Argentina.
  • 2 Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA) - Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Av Patricias Argentinas 435, C1405BWE Buenos Aires, Argentina.
  • 3 Department of Molecular and Cellular Biology and Physiology (FBMyC), Facultad de Ciencias Exactas y Naturales (FCEN), University of Buenos Aires (UBA), C1428EHA Buenos Aires, Argentina.
  • 4 Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal.
  • 5 Instituto de Física de Buenos Aires (IFIBA). Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires (UBA), C1428EHA Buenos Aires, Argentina.
  • 6 Departamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (UBA), C1428EHA Buenos Aires, Argentina.
  • 7 Instituto de Histología y Embriología (IHEM). Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Cuyo (UNCuyo), 5500, Mendoza, Argentina.
  • 8 Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Cuyo (UNCuyo), Mendoza, Argentina.
PMID: 39925132 DOI: 10.1242/jcs.263433
Abstract

Biomolecular condensates (BMCs) emerge as important players in RNA regulation. The RNA binding protein Smaug forms cytosolic BMCs in mammals, insects and yeasts and affects mitochondrial function and/or responses to nutrient deprivation. Here we found that the non-canonical activation of the SMO-AMPK pathway known to affect energy metabolism triggers the immediate disassembly of BMCs formed by a number of human and rodent Smaug orthologs, whereas processing bodies remained rather unaltered. A non-phosphorylatable Smo mutant abrogated the effect, involving Smo phosphorylation in hSmaug1 BMCs regulation. Three mechanistically different Smo ligands, namely SAG; GSA-10 and cyclopamine elicited a similar response, which was blocked upon AMPK pharmacological inhibition. Polysome disassembly by puromycin halted Smaug1 BMC dissolution, thus suggesting that unbound transcripts became translationally active. Single-molecule fluorescent in situ hybridization illustrated the release of UQCRC1 mRNA. Finally, Smaug1 is a phosphoprotein bound by 14-3-3 proteins and the competitive inhibitor difopein blocked the response to non-canonical Smo stimulation. We propose that the regulated condensation and dispersion of Smaug1 BMCs generate translational changes that contribute to metabolic regulation downstream of the non-canonical SMO-AMPK axis.

Keywords

Energy metabolism; Liquid-liquid phase separation; Membraneless organelle; Samd4a; Samd4b.

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