TTLL4 (tubulin tyrosine ligase-like 4) is a monoglutamylase that catalyzes the initiation of polyglutamylation, a post-translational modification adding single glutamate residues to target proteins 1. While initially characterized on tubulins—preferentially modifying β-tubulin [UniProt]—TTLL4 has broad substrate specificity including nucleosome assembly proteins (NAP1L1, NAP1L4), the cGAS innate immune sensor, and the pluripotency transcription factor KLF4 2. TTLL4-mediated KLF4 glutamylation protects it from ubiquitin-mediated degradation, promoting cell reprogramming and embryonic development 2. In neural tissue, TTLL4 is a key contributor to polyglutamylation-related neurodegeneration, with TTLL4 deficiency partially rescuing Purkinje cell and photoreceptor loss in polyglutamylation-imbalanced mice 3. TTLL4 activity is negatively regulated by NEK5-mediated phosphorylation 4. Clinically, TTLL4 overexpression in breast cancer associates with brain metastasis by enhancing β-tubulin polyglutamylation and multivesicular body trafficking, promoting blood-brain barrier disruption 5. Similarly, TTLL4 upregulation in pancreatic cancer correlates with PELP1 polyglutamylation and altered chr2 remodeling 6. These findings establish TTLL4 as a regulatory hub linking cytoskeletal dynamics to pluripotency, neuronal homeostasis, and cancer progression.