Clec16a, a membrane-associated C-type lectin protein functioning as an E3-ubiquitin ligase, is of great significance. It regulates autophagy, mitophagy, endocytosis, intracellular trafficking, and immune function, and is involved in processes like insulin secretion crucial for cellular homeostasis [1,4]. Genetic models, especially mouse models, have been instrumental in studying its functions.

Inducible whole-body knockout of Clec16a in mice (Clec16aΔUBC mice) led to a neuronal phenotype including tremors, impaired gait, and dystonic postures, along with loss of sensory axons, activation of microglia and astrocytes in the CNS, and changes in mitochondrial-related proteins and interferon stimulated gene 15 (IGS15) expression [3]. Clec16a inducible knockout (KO) mice also showed weight loss, thymic and splenic atrophy, with lowered mitochondrial potential in splenocytes, disrupted mitophagy in splenic B and T cells, and increased cytotoxicity in NK cells [5]. In astrocytes, Clec16a promotes mitophagy, and its inactivation in a multiple sclerosis mouse model worsened the disease by increasing activation of NF-κB, NLRP3, and gasdermin D [2].

In conclusion, Clec16a is essential for maintaining normal cellular functions, especially in relation to mitochondrial quality control through mitophagy. Mouse KO models have revealed its crucial role in neurodegeneration and autoimmune diseases, such as multiple sclerosis and conditions related to immune cell dysregulation. These findings enhance our understanding of the underlying mechanisms of these diseases and may guide the development of targeted therapies [1,2,3,5].