bims-nocaut Biomed News
on Non-canonical autophagy
Issue of 2025–06–22
two papers selected by
Quentin Frenger, University of Strasbourg



  1. Nat Struct Mol Biol. 2025 Jun 17.
      Lysosomes, central hydrolytic organelles, are regulated by ion flow, including calcium and protons, via transporters and channels to maintain an acidified lumen for hydrolytic activity. TRPML1, a lysosomal ion channel, effluxes cations upon activation, promoting rapid conjugation of ATG8 proteins to the lysosomal membrane in a process known as conjugation of ATG8 to single membranes (CASM). However, our understanding of how TRPML1 activation reorganizes the lysosomal proteome is poorly understood. Here, we identify DMXL1 as a key regulator of lysosomal homeostasis through quantitative proteomics of lysosomes during TRPML1 activation by the agonist MLSA5. DMXL1 is recruited to lysosomes and Salmonella-containing vacuoles, both in a CASM-dependent manner. As the mammalian ortholog of yeast Rav1, DMXL1 assembles with Rav2 ortholog ROGDI and WDR7, and associates with V0 and V1 subunits of the lysosomal V-ATPase. TRPML1 activation drives V1 subunit recruitment to lysosomes in a DMXL1- and DMXL2-dependent manner. DMXL1- and DMXL2-deficient cells display reduced V1-ATPase recruitment, increased lysosomal pH and diminished hydrolytic capacity. Using AlphaFold modeling supported by cross-linking proteomics, we identify interaction interfaces within the DMXL1-ROGDI-WDR7 complex, as well as an ATP6V1A binding interface in DMXL1, whose mutation affects interaction and function. Our findings suggest CASM-dependent DMXL1 recruitment, coupled with V-ATPase assembly, is critical for maintaining lumenal pH and lysosomal function in response to TRPML1 activation.
    DOI:  https://doi.org/10.1038/s41594-025-01581-x
  2. J Mol Biol. 2025 Jun 11. pii: S0022-2836(25)00354-7. [Epub ahead of print] 169288
      Autophagy proteins coordinate the biogenesis of a phagophore, the formation and maturation of an autophagosome. Genetic mutations of these proteins can result in dysregulated autophagy, stalled autophagosome biogenesis, and lead to cell death. ATG9, the sole transmembrane ATG (autophagy related) protein governs the nucleation of the phagophore. At a molecular level ATG9 has been shown to be a lipid scramblase capable of redistributing lipids across the lipid bilayer. ATG9-positive vesicles can also deliver lipid-modifying enzymes to alter the lipid composition of membranes. Both functions are required for autophagy. However, ATG proteins, including ATG9, play key molecular roles in pathways unrelated to autophagy. ATG9 has been shown to function in multiple pathways at the Golgi, plasma membrane, and lysosomes. ATG9 can also play an important role in immune signalling. The trafficking of ATG9 in ATG9-positive vesicles is essential to many of these pathways. In this review we highlight the functions of ATG9 in autophagy and autophagy-unrelated pathways, here referred to as "non-canonical functions", and summarise the broader role of ATG9A in cell homeostasis.
    Keywords:  ATG9A; Atg9; autophagy; membrane trafficking
    DOI:  https://doi.org/10.1016/j.jmb.2025.169288