TULP3

Tubby-like protein 3 (TULP3), a member of the Tubby family of bipartite transcription factors, functions as an adaptor protein regulating membrane receptor trafficking and ciliary signaling. Also termed TUBL3, it contains a conserved C-terminal Tubby domain for phosphoinositide binding and an N-terminal domain interacting with the retrograde trafficking complex (Retromer) and G protein-coupled receptors (GPCRs). TULP3 facilitates the ciliary localization of specific GPCRs, including Smoothened (SMO), thereby modulating Hedgehog (Hh) signaling. It also represses mTORC1 activity by stabilizing TSC1-TSC2 complexes, linking ciliary dysfunction to metabolic regulation. Mutations in TULP3 are associated with ciliopathies such as retinitis pigmentosa, obesity, and neurodevelopmental disorders. While no direct TULP3-targeted therapies exist, pharmacological inhibitors of Hh signaling (e.g., vismodegib) or mTOR (e.g., rapalogs) may indirectly address TULP3-related pathologies. Recent studies highlight its potential role in tumor suppression via cilia-dependent signaling restraint.