bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2026–08–23
two papers selected by
Irene Sambri, TIGEM
  1. Substrate-specific regulation of the mTORC1 pathway by G protein-coupled receptors.
  2. Modelling ischaemic AKI in human kidney organoids reveals injury-associated epithelial states and macrophage-epithelial crosstalk.
  1. Biochem J. 2026 Aug 19. pii: BCJ20260165. [Epub ahead of print]
    Substrate-specific regulation of the mTORC1 pathway by G protein-coupled receptors.
    Samuel J Atkinson, Florentina Negoita, Yuichiro Ioi, William Vincent Ritchie, Kyle Thompson, Max Gardner, Peter T Ashdown, Kristina Hellberg, Terunao Takahara, Kei Sakamoto, Dawn Thompson, James N Hislop, Riko Hatakeyama.
      The mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) orchestrates cell growth and metabolism in response to diverse extracellular and intracellular cues. mTORC1 phosphorylates a broad range of substrates, each of which plays important physiological roles. Emerging evidence suggests that mTORC1 can respond to upstream signals in a nuanced manner, enabling differential regulation of individual substrates and, consequently, specific downstream biological processes. Phosphorylation of non-canonical mTORC1 substrates, such as the lysosome biogenesis regulator transcription factor EB (TFEB), can be regulated independently of phosphorylation of canonical substrates. However, the nature of signals that determine the signaling selectivity of mTORC1 remains incompletely understood. Here, we studied mTORC1 regulation by G protein-coupled receptors (GPCRs). We found that phosphorylation of TFEB responds to GPCRs differently, compared to canonical mTORC1 substrates controlling protein synthesis such as S6K1 and 4EBP1. In particular, the muscarinic acetylcholine receptor M5 (M5R) promoted phosphorylation of S6K1 and 4EBP1, while triggering TFEB dephosphorylation. Consequently, M5R stimulated protein synthesis without inhibiting lysosome biogenesis. mTORC1 can thus separately regulate anabolic and catabolic processes under the control of M5R. This study highlights the importance of reassessing the effects of GPCRs on mTORC1 by concurrently monitoring individual substrates, a critical consideration to be made when evaluating GPCR ligands as therapeutic agents targeting the mTORC1 pathway.
    Keywords:  G protein-coupled receptor (GPCR); mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1); muscarinic acetylcholine receptor M5 (M5R)
    DOI:  https://doi.org/10.1042/BCJ20260165
  2. Genome Med. 2026 Aug 19. pii: 119. [Epub ahead of print]18(1):
    Modelling ischaemic AKI in human kidney organoids reveals injury-associated epithelial states and macrophage-epithelial crosstalk.
    Ana B Nunez-Nescolarde, Yang Liao, Laura Perlaza-Jiménez, Mehran Piran, Zhengqi Cheng, Chris K Barlow, Joel R Steele, Deanna Deveson, Julie L M Moreau, Han-Chung Lee, Jinhua Li, Ralf B Schittenhelm, Christine A Wells, Wei Shi, David J Nikolic-Paterson, Alexander N Combes.
       BACKGROUND: Acute kidney injury (AKI) is a common clinical syndrome associated with high morbidity and progression to chronic kidney disease. Ischaemia is a leading cause of AKI, driving cellular stress, metabolic reprogramming, and injury-associated epithelial states. Scalable human models that enable controlled investigation of ischaemic injury, repair, and therapeutic targets in AKI remain limited. We therefore assessed the extent to which induced pluripotent stem cell (iPSC)-derived human kidney organoids recapitulate key features of ischaemic AKI.
    METHODS: Kidney organoids were subjected to hypoxic injury (1% O₂, 48 h) followed by normoxic recovery. Transcriptomic, proteomic, metabolomic, single-cell, and spatial profiling were performed across acute injury and recovery phases. iPSC-derived macrophages were integrated into organoids and analysed following hypoxic injury.
    RESULTS: Hypoxia induced acute stress responses, including hypoxia-inducible factor activation, glycolytic reprogramming, cell cycle arrest, and induction of injury markers. Following recovery, organoids exhibited sustained inflammatory signalling and persistent metabolic dysregulation. Single-cell analysis revealed loss of cell type-specific markers and key functional genes across nephron segments. After return to normoxia, podocyte and distal tubule markers were largely restored, whereas proximal tubule markers showed only partial recovery. Injury-associated and inflammatory programs persisted across all nephron cell types, including upregulation of GDF15, MMP7, SPP1, CXCL2, and ICAM1, with enrichment of complement, TNF-NFκB, and lipid-associated inflammatory pathways. Injured proximal tubules were enriched for adaptive/maladaptive repair signatures derived from human kidney biopsies and displayed heterogeneous recovery. While some cells restored canonical identity, others retained dedifferentiated injury-associated states, including focal expression of CDKN1A and VCAM1. Integrated macrophages transitioned from homeostatic, resident-like profiles to activated phenotypes following injury, exhibiting spatially localised interactions with injured tubules and increased expression of cytokines, chemokines, and matrix-remodelling factors.
    CONCLUSIONS: Human kidney organoids recapitulate key epithelial features of hypoxic injury, including segment-specific vulnerability, persistent inflammatory signalling, and heterogeneous recovery, with integrated macrophages adopting activated inflammatory states following injury. While constrained by developmental immaturity, this system provides a tractable human platform to investigate injury-associated epithelial states and macrophage-epithelial crosstalk in AKI.
    Keywords:  Acute kidney injury; Epithelial repair; Hypoxia; Injury-associated cell states; Ischemic acute kidney injury; Kidney organoids; Macrophages; Metabolic reprogramming; Single-cell transcriptomics; Spatial transcriptomics
    DOI:  https://doi.org/10.1186/s13073-026-01712-z
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