bims-nocaut 2023-11-26 papers

Issue of 2023‒11‒26
two papers selected by
Quentin Frenger, University of Strasbourg

Autophagy. 2023 Nov 24.

Deacetylation of ATG7 drives the induction of macroautophagy and LC3-associated microautophagy.

Yinfeng Xu, Chuying Qian, Qian Wang, Lijiang Song, Zhengfu He, Wei Liu, Wei Wan.

LC3 lipidation plays an important role in the regulation of macroautophagy and LC3-associated microautophagy. The E1-like enzyme ATG7 is one of the core components that are directly involved in LC3 lipidation reaction. Here, we provide evidence showing that acetylation of ATG7 tightly controls its enzyme activity to regulate the induction of macroautophagy and LC3-associated microautophagy. Mechanistically, acetylation of ATG7 disrupts its interaction with the E2-like enzyme ATG3, leading to an inhibition of LC3 lipidation in vitro and in vivo. Functionally, in response to various different stimuli, cellular ATG7 undergoes deacetylation to induce macroautophagy and LC3-associated microautophagy, which are necessary for cells to eliminate cytoplasmic DNA and degrade lysosome membrane proteins, respectively. Taken together, these findings reveal that ATG7 acetylation acts as a critical rheostat in controlling LC3 lipidation and related cellular processes.

Keywords: ATG7; Acetylation; LC3 lipidation; macroautophagy; microautophagy

DOI: https://doi.org/10.1080/15548627.2023.2287932

EMBO Mol Med. 2023 Nov 22. e17815

Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation.

Ming-Yue Wu, Yun-Jun Ge, Er-Jin Wang, Qi-Wen Liao, Zheng-Yu Ren, Yang Yu, Guoyuan Zhu, Chun-Ping Liu, Meng-Ni Zhang, Huanxing Su, Han-Ming Shen, Ye Chen, Lei Wang, Yi-Tao Wang, Min Li, Zhaoxiang Bian, Jin Chai, Richard D Ye, Jia-Hong Lu.

Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits therapeutic potential for inflammation resolution and tissue repair. However, pharmacological approaches to enhance efferocytosis remain sparse due to a lack of targets for modulation. Here, we report the identification of columbamine (COL) which enhances macrophage-mediated efferocytosis and attenuates intestinal inflammation in a murine colitis model. COL enhances efferocytosis by promoting LC3-associated phagocytosis (LAP), a non-canonical form of autophagy. Transcriptome analysis and pharmacological characterization revealed that COL is a biased agonist that occupies a part of the ligand binding pocket of formyl peptide receptor 2 (FPR2), a G-protein coupled receptor involved in inflammation regulation. Genetic ablation of the Fpr2 gene or treatment with an FPR2 antagonist abolishes COL-induced efferocytosis, anti-colitis activity and LAP. Taken together, our study identifies FPR2 as a potential target for modulating LC3-associated efferocytosis to alleviate intestinal inflammation and highlights the therapeutic value of COL, a natural and biased agonist of FPR2, in the treatment of inflammatory bowel disease.

Keywords: FPR2; LC3-associated efferocytosis; columbamine; inflammatory bowel disease

DOI: https://doi.org/10.15252/emmm.202317815