Clec16a, a membrane-associated C-type lectin protein functioning as an E3-ubiquitin ligase, is emerging as a crucial genetic factor. It plays a critical role in regulating autophagy, mitophagy, endocytosis, intracellular trafficking, and immune function. These processes are essential for cellular homeostasis, insulin secretion, and more [1,3]. Genetic models, such as mouse models, have been instrumental in studying its functions.

Inducible whole-body knockout (Clec16aΔUBC) mice exhibited a neuronal phenotype with tremors, impaired gait, and sensory axon loss, along with activated microglia and astrocytes in the CNS, resembling spinocerebellar ataxia [2]. In Clec16a inducible knockout (KO) mice, there was weight loss, thymic and splenic atrophy, disrupted mitophagy in splenic B and T cells, and increased NK cell cytotoxicity, suggesting a link between Clec16a loss-of-function and inflammation in autoimmunity [4]. Also, two mouse strains with independent Clec16a mutations developed neurodegenerative disease, showing abnormal autolysosome function and Purkinje cell loss [5].

In conclusion, Clec16a is essential for maintaining cellular homeostasis through its regulation of multiple cellular processes. Mouse KO models have revealed its significance in neurodegeneration and autoimmunity, providing insights into the underlying mechanisms of these diseases and potential therapeutic targets.