bims-lycede 2025-12-21 papers

Science. 2025 Dec 18. 390(6779): eaee5883

Erratum for the Report "TFEB links autophagy to lysosomal biogenesis" by C. Settembre et al.

DOI: https://doi.org/10.1126/science.aee5883

J Cell Biol. 2026 Feb 02. pii: e202501135. [Epub ahead of print]225(2):

Maspardin/SPG21 controls lysosome motility and TFEB phosphorylation through RAB7 positioning.

Thomas Jacqmin, Florentine Gilis, Martine Albert, Jean-François Gaussin, Michel Jadot, Marielle Boonen.

Spastic paraplegia 21 is a neurodegenerative disease characterized by the degeneration of corticospinal axons. It is caused by mutations in the SPG21 gene, which encodes maspardin, a cytosolic protein of unknown function that associates with the late endosomal/lysosomal membrane. Intriguingly, we found that the phosphorylation level of the transcription factor EB (TFEB), a master regulator of the CLEAR gene network, is decreased in SPG21 knockout cells, leading to TFEB nuclear translocation. Our investigations revealed that the Rag-mediated presentation of TFEB to the mTOR kinase and its subsequent phosphorylation is disturbed by a delocalization of the RAB7 GTPase, a maspardin-binding partner, from retromer-positive late endosomes to lysosomes. This redistribution decreases the interaction between RAB7 and its GTPase-activating protein (GAP), TBC1D5. Consequently, RAB7 remains primarily GTP-bound, recruiting more FYCO1 to lysosomes and promoting the anterograde movement of these organelles along microtubules. These findings identify maspardin as a newly discovered RAB7 effector and shed light on several consequences of its deficiency.

DOI: https://doi.org/10.1083/jcb.202501135

bioRxiv. 2025 Nov 26. pii: 2025.11.24.690233. [Epub ahead of print]

cAMP promotes acute lysosome biogenesis through TFEB nuclear import-export dynamics.

Saumya Bhatt, Mohammad Ali Abbas Zaidi, Nicholas Woods, Cody N Rozeveld, Micah B Schott.

Cyclic adenosine monophosphate (cAMP) signaling is a major stimulus for lipid and glucose catabolism, yet catabolic processes like these can also coordinate with lysosome-dependent degradation. However, the impact of cAMP signaling on lysosomal dynamics remains unclear. Transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, is regulated by stimulus-dependent nuclear-cytoplasmic shuttling through a variety of phosphorylation events. Here, we find that elevating intracellular cAMP with forskolin and IBMX induces rapid nuclear import of TFEB-GFP within 30 minutes and coincides with a transient upregulation of TFEB target lysosome genes. By 8 hours, TFEB returns to the cytoplasm, accompanied by transcriptional downregulation. Inhibition of cAMP-dependent protein kinase A (PKA) using H89 did not block nuclear import but unexpectedly caused sustained nuclear accumulation, indicating that PKA promotes TFEB nuclear export. Consistent with this, phosphoproteomic profiling revealed increased phosphorylation of a PKA-consensus motif (RRx S) during the export phase. These findings suggest that cAMP-PKA signaling plays a novel role in temporally "tuning" lysosomal gene expression by regulating TFEB nuclear-cytoplasmic shuttling.
Summary: This study reveals that cAMP signaling dynamically regulates TFEB subcellular localization, promoting transient, calcium-dependent nuclear import as well as downstream, PKA-dependent export and phosphorylation at serines 466/467. These findings uncover a novel mechanism by which cAMP stimulation fine-tunes lysosomal gene expression by regulating TFEB nuclear import and export.

DOI: https://doi.org/10.1101/2025.11.24.690233