TTLL6-mediated Polyglutamylation of PurA Maintains Colonic Crypt Integrity

The tubulin tyrosine ligase–like (TTLL) family comprises enzymes catalyzing posttranslational modifications of tubulin, including glutamylation and glycylation. We previously described a critical role for the monoglycylase TTLL3 in colon. Here, we identified TTLL6 as the predominant polyglutamylase in the colon, specifically expressed in epithelial cells of distal and transverse segments. TTLL6 expression decreases during CRC progression, correlating with poor patient prognosis. Deletion of Ttll6 in mice resulted in elongated colonic crypts, expansion of stem and transit-amplifying compartments, and increased numbers of differentiated epithelial cells. Moreover, Ttll6 -deficient mice showed an elevated susceptibility to chemically induced colon carcinogenesis. Notably, we identified the nucleic acid–binding protein PurA as a novel TTLL6 substrate with both proteins mutually required for nuclear localization. Consistently, both nuclear polyglutamylation and PurA were present in the bottom compartment of control colons, but reduced in Ttll6 -deficient colons. These findings reveal a TTLL6-PurA axis being critical in maintaining colonic homeostasis.