bims-nocaut Biomed News
on Non-canonical autophagy
Issue of 2025–07–27
two papers selected by
Quentin Frenger, University of Strasbourg
  1. ATG8ylation-mediated tonoplast invagination mitigates vacuole damage.
  2. Secretory autophagy mediates lysosomal and autophagic degradation for α-synuclein proteostasis.
  1. Nat Commun. 2025 Jul 18. 16(1): 6621
    ATG8ylation-mediated tonoplast invagination mitigates vacuole damage.
    Xuanang Zheng, Juncai Ma, Jing Li, Siyu Chen, Jun Luo, Jianxiong Wu, Kaiyan Zhang, Changlian Peng, Yonglun Zeng, Faqiang Li, Byung-Ho Kang, Caiji Gao, Jun Zhou.
      While ATG8ylation, the lipidation of ATG8-family proteins, is canonically linked to double-membrane autophagosome formation, emerging studies demonstrate its non-canonical association with single-membrane organelles. The functional significance of ATG8ylation in these compartments, however, remains unclear. Here, we demonstrate that ionophores rapidly trigger ATG8 conjugation to the vacuolar membrane (tonoplast), a process reliant on the ATG conjugation system rather than the upstream autophagic regulators. Inhibiting reactive oxygen species (ROS) generation or V-ATPase function greatly impedes the targeting of ATG8 to the tonoplast. Intriguingly, the attachment of ATG8 to the tonoplast enhances its invagination and fosters the formation of intraluminal vesicles within vacuoles, which is achieved independently of the ESCRT machinery or cytoskeletal components. The emergence of ATG8-positive vesicles may facilitate the restoration of vacuolar acidification by redirecting proton flow from the vacuole-to-cytoplasm to an intravacuolar direction, which aids in the rapid recovery of plant growth after removal of monensin. Furthermore, under alkaline stress, ATG8 targets the tonoplast and induces vacuolar membrane invagination via a regulatory mechanism similar to that of monensin, indicating that ATG8ylation-mediated vacuolar remodeling represents an adaptive mechanism against environmental alkalinization in plants.
    DOI:  https://doi.org/10.1038/s41467-025-62084-3
  2. J Biol Chem. 2025 Jul 17. pii: S0021-9258(25)02324-5. [Epub ahead of print] 110474
    Secretory autophagy mediates lysosomal and autophagic degradation for α-synuclein proteostasis.
    Taiki Sawai, Yoshitsugu Nakamura, Shigeki Arawaka.
      Autophagy has two distinct pathways, degradation and secretion. Autophagic degradation plays a pivotal role in proteostasis. However, the role of autophagic secretion in proteostasis maintenance is not fully understood. Here, we investigate how the blockade of autophagic secretion impairs proteostasis in SH-SY5Y cells. siRNA-mediated knockdown of a modulator for autophagosome formation, ATG5, BECN1 or FIP200 inhibited autophagic flux and secretion, causing accumulation of Triton X-100-insoluble α-synuclein, which is an aggregate-prone protein responsible for neuronal loss in Parkinson's disease. The blockade of autophagic secretion by knockdown of t-SNARE SNAP23 or STX4 increased autophagic flux for p62 degradation, but these knockdowns induced enlargement and membrane damage of lysosomes as well as lysosomal dysfunction. SNAP23 or STX4 knockdown caused accumulation of Triton X-100-insoluble α-synuclein against induction of lysophagy. GBA knockdown showed lysosomal damage with the increase in autophagic secretion. RAB8A, a small GTPase regulator of polarized sorting to the plasma membrane, knockdown blocked autophagic secretion and produced lysosomal damage. SNAP23, STX4 or RAB8A knockdown further accelerated accumulation of Triton X-100-insoluble α-synuclein caused by a lysosomal protease inhibitor cocktail. Collectively, these findings suggest that SNAP23, STX4 or RAB8A knockdown blocks autophagic secretion and upregulates autophagic flux as a compensatory response to help maintain degradation. However, these knockdowns impair α-synuclein proteostasis because of lysosomal damage that they induce, counteracting compensatory effects of autophagic degradation, including lysophagy. Autophagic secretion and degradation may collaboratively form the clearance pathway required for maintaining lysosomal function by reducing the burden of aggregate-prone protein cargo.
    Keywords:  Parkinson disease; autophagy; lysosome; protein secretion; proteostasis; synuclein
    DOI:  https://doi.org/10.1016/j.jbc.2025.110474
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