Ttll4, short for Tubulin Tyrosine Ligase-like 4, is a key enzyme involved in polyglutamylation, a post-translational modification process. It adds glutamate residues to substrate proteins, which is crucial for various biological processes. Polyglutamylation is associated with pathways related to cytoskeleton regulation, chromatin remodeling, and cell-fate determination, thereby being of great biological importance. Genetic models, such as knockout mouse models, are valuable tools for studying Ttll4 [1,3,4,5,6,7,8,9].

In pcd mice, a model of neurodegeneration, loss of Ttll4 attenuates the degeneration of Purkinje and mitral cells, and partially rescues photoreceptor degeneration and impaired rhodopsin trafficking, indicating its role in neurodegenerative phenotypes [1]. In breast cancer cells, overexpression of Ttll4 is associated with brain metastasis and alters exosome biogenesis [2]. Ttll4-knockout mice show larger average RBC diameters, greater vulnerability to oxidative stress, and cytoskeletal component aggregation in red blood cells, suggesting its importance in proper cytoskeletal organization in RBCs [3]. In pancreatic cancer cells, knockdown of Ttll4 attenuates cell growth, while exogenous introduction enhances it, and Ttll4 is involved in PELP1 polyglutamylation and chromatin remodeling [6]. In addition, Ttll4 -/- mice have reduced IL-7Rα polyglutamylation and Sall3 expression in common helper-like innate lymphoid progenitors, affecting group 3 ILC development [7]. Also, deletion of Ttll4 abrogates cell reprogramming and early embryogenesis as Klf4 polyglutamylation by Ttll4 is required for these processes [9].

In conclusion, Ttll4 plays essential roles in multiple biological processes, including neurodegeneration, cancer metastasis, cytoskeletal organization, cell-fate determination during lymphoid cell development, and early embryonic development. The Ttll4 knockout mouse models have significantly contributed to understanding its functions in these disease-related areas, providing insights into the underlying mechanisms and potential therapeutic targets.