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    Proper cytoskeletal architecture beneath the plasma membrane of red blood cells requires . Ijaz Faryal,Hatanaka Yasue,Hatanaka Takahiro,Tsutsumi Koji,Iwaki Takayuki,Umemura Kazuo,Ikegami Koji,Setou Mitsutoshi Molecular biology of the cell Mammalian red blood cells (RBCs) circulate through blood vessels, including capillaries, for tens of days under high mechanical stress. RBCs tolerate this mechanical stress while maintaining their shape because of their elastic membrane skeleton. This membrane skeleton consists of spectrin-actin lattices arranged as quasi-hexagonal units beneath the plasma membrane. In this study, we found that the organization of the RBC cytoskeleton requires tubulin tyrosine ligase-like 4 (). RBCs from -knockout mice showed larger average diameters in smear test. Based on the rate of hemolysis, -knockout RBCs showed greater vulnerability to phenylhydrazine-induced oxidative stress than did wild-type RBCs. Ultrastructural analyses revealed the macromolecular aggregation of cytoskeletal components in RBCs of -knockout mice. Immunoprecipitation using the anti-glutamylation antibody GT335 revealed nucleosome assembly protein 1 (NAP1) to be the sole target of TTLL4 in the RBCs, and NAP1 glutamylation was completely lost in -knockout RBCs. In wild-type RBCs, the amount of glutamylated NAP1 in the membrane was nearly double that in the cytosol. Furthermore, the absence of TTLL4-dependent glutamylation of NAP1 weakened the binding of NAP1 to the RBC membrane. Taken together, these data demonstrate that is required for proper cytoskeletal organization in RBCs. 10.1091/mbc.E16-02-0089