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]. Although ATG16L1 has been more extensively studied, ATG16L2 is also implicated in diseases like cancer, inflammatory bowel diseases, and neurodegenerative disorders [1].

ATG16L2 -deficient macrophages show attenuated LPS-induced autophagy flux, elevated NLRP3 inflammasome activation, and defects in mitochondrial integrity and respiration [2]. ATG16L2 knockout mice are more susceptible to DSS-induced intestinal damage, which can be improved by inhibiting NLRP3 [2]. Also, ATG16L2-deficient macrophages exhibit reduced NLRC4 inflammasome activation, and ATG16L2-knockout mice infected with Salmonella typhimurium have decreased pathogen clearance and survival rates [3]. In melanoma cells, knockdown of ATG16L2 results in increased autophagy and apoptosis [4]. In pancreatic β-cells, NR3C1 activation upregulates FTO, which reduces m6A modifications on Atg16l2 mRNA and leads to hyperactive autophagy [5]. In the Chinese population, a SNP (rs11235604) of ATG16L2 is associated with down-regulation of its expression and is a susceptibility factor for Crohn's disease [6].

In conclusion, ATG16L2 plays important roles in autophagy, inflammasome regulation, and apoptosis, which are associated with various diseases such as inflammatory bowel diseases, cancer, and diabetes. Gene knockout mouse models have been valuable in revealing these functions, helping us understand the mechanisms of disease occurrence and providing potential targets for treatment.