PDE6D is a 17 kDa phosphodiesterase that functions as a guanine nucleotide dissociation inhibitor (GDI) for prenylated proteins, particularly farnesylated and palmitoylated cargo molecules 1. Primary function: PDE6D releases prenylated proteins from cellular membranes and modulates their subcellular localization by binding to GTP-bound small GTPases, stabilizing ARL3-GTP and increasing its GTP affinity 2. Mechanism: PDE6D recruits and transports prenylated ciliary cargo, including INPP5E, NIM1K, and UBL3, to primary cilia through its interaction with ciliary targeting complexes containing RPGR, ARL13B, and TULP3 32. Disease relevance: Mutations in PDE6D cause Joubert syndrome 22 (JBTS22), a ciliopathy characterized by cerebellar abnormalities 4. PDE6D dysfunction also leads to photoreceptor degeneration and retinal damage in mice 2. Clinical significance: PDE6D represents a therapeutic target in castration-resistant prostate cancer, where PDE6D degradation enhances metformin sensitivity and activates cGMP/PKG signaling pathways 5. Small molecule degraders like TMX-4100 have been developed to selectively target PDE6D 6.