bims-nocaut 2024-06-02 papers

Issue of 2024‒06‒02
two papers selected by
Quentin Frenger, University of Strasbourg

Autophagy. 2024 May 31. 1-3

Vesicle-vesicle fusion promoted by the Atg8-family autophagy protein LC3C: relevance of the N-terminal region.

Uxue Ballesteros, Alicia Alonso, L Ruth Montes, Asier Etxaniz.

Among the MAP1LC3/LC3 subfamily of Atg8 proteins, LC3B and LC3C constitute the most and least studied members, respectively, LC3B being generally considered as an autophagosomal marker and a canonical representative of the LC3 subfamily. In several recent studies, LC3C has emerged as an important modulator in various processes of cell homeostasis. Our own research data demonstrate that LC3C induces higher levels of tethering and of intervesicular lipid mixing than LC3B. LC3C contains a peculiar N-terminal region, different from the other Atg8-family protein members. Using a series of mutants, we have shown that the N-terminal region of LC3C is responsible for the enhanced vesicle tethering, membrane perturbation and vesicle-vesicle fusion activities of LC3C as compared to LC3B.Abbreviations: ATG: autophagy related; GABARAP: gamma-aminobutyric acid receptor associated protein; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PC: phosphatidyl choline; PE: phosphatidylethanolamine; PEmal: maleimide-derivatized PE; PtdIns: phosphatidylinositol.

Keywords: Atg8; LC3C; N terminus; autophagy proteins; vesicle fusion

DOI: https://doi.org/10.1080/15548627.2024.2359354

EMBO J. 2024 May 28.

LC3-associated phagocytosis of neutrophils triggers tumor ferroptotic cell death in glioblastoma.

Tong Lu, Patricia P Yee, Stephen Y Chih, Miaolu Tang, Han Chen, Dawit G Aregawi, Michael J Glantz, Brad E Zacharia, Hong-Gang Wang, Wei Li.

Necrosis in solid tumors is commonly associated with poor prognostic but how these lesions expand remains unclear. Studies have found that neutrophils associate with and contribute to necrosis development in glioblastoma by inducing tumor cell ferroptosis through transferring myeloperoxidase-containing granules. However, the mechanism of neutrophilic granule transfer remains elusive. We performed an unbiased small molecule screen and found that statins inhibit neutrophil-induced tumor cell death by blocking the neutrophilic granule transfer. Further, we identified a novel process wherein neutrophils are engulfed by tumor cells before releasing myeloperoxidase-containing contents into tumor cells. This neutrophil engulfment is initiated by integrin-mediated adhesion, and further mediated by LC3-associated phagocytosis (LAP), which can be blocked by inhibiting the Vps34-UVRAG-RUBCN-containing PI3K complex. Myeloperoxidase inhibition or Vps34 depletion resulted in reduced necrosis formation and prolonged mouse survival in an orthotopic glioblastoma mouse model. Thus, our study unveils a critical role for LAP-mediated neutrophil internalization in facilitating the transfer of neutrophilic granules, which in turn triggers tumor cell death and necrosis expansion. Targeting this process holds promise for improving glioblastoma prognosis.

Keywords: Ferroptosis; Glioblastoma; LC3-associated Phagocytosis; Neutrophil; Tumor Necrosis

DOI: https://doi.org/10.1038/s44318-024-00130-4