Ttll1, short for tubulin tyrosine ligase-like 1, is a member of the tubulin tyrosine ligase superfamily. It is involved in the post-translational polyglutamylation of tubulin in axonemal microtubules within cilia and flagella, which is crucial for regulating microtubule dynamics and function [3,4]. Polyglutamylation is part of a dynamic process where glutamate residues are added to substrate proteins by TTLL family members and removed by carboxypeptidases, and it plays important roles in various biological processes [1].

In gene-knockout mouse models, Ttll1 deficiency has multiple effects. In pcd mice (mutants of the gene encoding Nna1/CCP1), loss of Ttll1 attenuates Purkinje cell loss and function, reduces olfactory bulb mitral cell death and retinal photoreceptor degeneration. It also rescues impaired rhodopsin trafficking to the rod outer segment in pcd mice [1]. In addition, Ttll1-KO mice show mucus accumulation in the nasal cavity due to impaired ciliary motility, leading to enhanced antigen-specific nasal IgA immune responses when intra-nasally immunized with certain vaccines [2]. On the contrary, Ttll1-KO mice nasally immunized with a claudin-4-targeting nasal vaccine show reduced PspA-specific nasal IgA responses because the mucus blocks vaccine binding [5]. Ttll1-deficient male mice are infertile due to abnormal sperm flagella development and immotility, while females are fertile [4].

In conclusion, Ttll1 is essential for normal motility of respiratory cilia, biogenesis and function of sperm flagella, and plays important roles in neurodegenerative processes and immune responses related to nasal mucosal vaccines. The gene-knockout mouse models of Ttll1 have provided valuable insights into its functions in these biological processes and related disease-like conditions such as neurodegeneration, chronic rhinosinusitis, and male infertility.