Yoichiro Abe

Aquaporin‐4 (AQP4) is a dominant water channel in the brain and is expressed on astrocytic end‐feet, mediating water homeostasis in the brain. AQP4 is a target of an inflammatory autoimmune disease, neuromyelitis optica spectrum disorders (NMOSD), that causes demyelination. An autoantibody recognizing the extracellular domains of AQP4, called NMO‐IgG, is critically implicated in the pathogenesis of the disease. Complement‐dependent cytotoxicity (CDC) and antibody‐dependent cellular cytotoxicity (ADCC) in astrocytes are the primary causes of the disease, preceding demyelination and neuronal damage. Additionally, some cytotoxic effects of binding of NMO‐IgG to AQP4, independent of CDC/ADCC, have been proposed. Antibody‐induced endocytosis of AQP4 is thought to be involved in CDC/ADCC‐independent cytotoxicity induced by the binding of NMO‐IgG to AQP4. To clarify the mechanism responsible for antibody‐induced endocytosis of AQP4, we investigated the subcellular localization and trafficking of AQP4, focusing on its C‐terminal domain, by making a variety of deletion and substitution mutants of mouse AQP4. We found that a tyrosine‐based YXXΦ motif in the C‐terminal domain of AQP4 plays a critical role in the steady‐state subcellular localization/turnover and antibody‐induced endocytosis/lysosomal degradation of AQP4. Our results indicate that the YXXΦ motif has to escape the inhibitory effect of the C‐terminal 10‐amino‐acid sequence and be located at an appropriate distance from the plasma membrane to act as a signal for lysosomal degradation of AQP4. In addition to lysosomal degradation, we demonstrated that the YXXΦ motif also functions as a signal to degrade AQP4 using proteasomes under specific conditions.