Unconventional secretion of tubby and tubby-like protein 1

Tubby-like proteins (Tulps) with no signal peptide have been characterized as cytoplasmic proteins with various intracellular functions, including binding to phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. PI(4,5)P2 has been implicated in unconventional secretion of fibroblast growth factor-2 without a signal peptide. Here, we show that all Tulps are expressed intracellularly and extracellularly. Tubby secretion is partially dependent on its PI(4,5)P2-binding activity with an essential secretory signal in the N-terminus. Pathogenic mutation in Tubby mice has no impact on tubby extracellular trafficking. Moreover, unconventional secretion of tubby and Tulp1 is independent of endoplasmic reticulum–Golgi pathway. These data implicate that Tulps may function extracellularly as well.