ATG16L2, an autophagic protein and a paralog of ATG16L1, is involved in autophagy, a fundamental cell process crucial for nutrient recycling and defense against pathogens (xenophagy) [1]. It has been associated with various diseases including cancer, inflammatory bowel diseases, and neurodegenerative disorders [1]. The generation of ATG16L2 knockout mouse models has been valuable in understanding its function [5].

In macrophages, ATG16L2 deficiency attenuates LPS-induced autophagy flux by mediating ATG5-12-16L1 complex assembly. ATG16L2-deficient macrophages also show elevated NLRP3 inflammasome activation, defects in mitochondrial integrity and respiration. ATG16L2 knockout mice are more susceptible to DSS-induced intestinal damage, which can be improved by inhibiting NLRP3, indicating that ATG16L2 positively regulates autophagy and could be a target for inflammatory diseases [2]. Additionally, ATG16L2-deficient macrophages have reduced NLRC4 inflammasome activation, and ATG16L2 knockout mice infected with Salmonella typhimurium have decreased pathogen clearance and survival rates, suggesting ATG16L2 is a significant modulator of the innate immune system [3]. In the context of cancer, ATG16L2 overexpression in colorectal cancer is associated with a good prognosis, and it can negatively affect CRC cell proliferation in vitro and in vivo [4].

In conclusion, ATG16L2 plays important roles in autophagy and innate immune responses. Model-based research, especially using ATG16L2 knockout mouse models, has revealed its functions in diseases such as inflammatory bowel diseases and colorectal cancer, providing insights into potential therapeutic targets for these diseases.

References:

1. Don Wai Luu, Laurence, Kaakoush, Nadeem O, Castaño-Rodríguez, Natalia. 2022. The role of ATG16L2 in autophagy and disease. In Autophagy, 18, 2537-2546. doi:10.1080/15548627.2022.2042783. https://pubmed.ncbi.nlm.nih.gov/35239457/

2. Wang, Dongyang, Yuan, Tianli, Liu, Jiamin, Wang, Zheng, Wu, Xuefeng. 2022. ATG16L2 inhibits NLRP3 inflammasome activation through promoting ATG5-12-16L1 complex assembly and autophagy. In European journal of immunology, 52, 1321-1334. doi:10.1002/eji.202149764. https://pubmed.ncbi.nlm.nih.gov/35426127/

3. Wen, Zhoujin, Yuan, Tianli, Liu, Jiamin, Wu, Xuefeng, Wang, Zheng. 2024. Atg16l2 augments Nlrc4 inflammasome activation by facilitating NAIPs-NLRC4 association. In European journal of immunology, 54, e2451078. doi:10.1002/eji.202451078. https://pubmed.ncbi.nlm.nih.gov/39175123/

4. Tang, Jian, Wang, Dongyang, Shen, Yuguang, Xue, Feng. . ATG16L2 overexpression is associated with a good prognosis in colorectal cancer. In Journal of gastrointestinal oncology, 12, 2192-2202. doi:10.21037/jgo-21-495. https://pubmed.ncbi.nlm.nih.gov/34790384/

5. Khor, Bernard, Conway, Kara L, Omar, Abdifatah S, Regev, Aviv, Xavier, Ramnik J. 2019. Distinct Tissue-Specific Roles for the Disease-Associated Autophagy Genes ATG16L2 and ATG16L1. In Journal of immunology (Baltimore, Md. : 1950), 203, 1820-1829. doi:10.4049/jimmunol.1800419. https://pubmed.ncbi.nlm.nih.gov/31451676/