title: Unconventional secretion of tissue transglutaminase involves phospholipid-dependent delivery into recycling endosomes.
abstract: Although endosomal compartments have been suggested to play a role in unconventional protein secretion, there is scarce experimental evidence for such involvement. Here we report that recycling endosomes are essential for externalization of cytoplasmic secretory protein tissue transglutaminase (tTG). The de novo synthesized cytoplasmic tTG does not follow the classical ER/Golgi-dependent secretion pathway, but is targeted to perinuclear recycling endosomes, and is delivered inside these vesicles prior to externalization. On its route to the cell surface tTG interacts with internalized β1 integrins inside the recycling endosomes and is secreted as a complex with recycled β1 integrins. Inactivation of recycling endosomes, blocking endosome fusion with the plasma membrane, or downregulation of Rab11 GTPase that controls outbound trafficking of perinuclear recycling endosomes, all abrogate tTG secretion. The initial recruitment of cytoplasmic tTG to recycling endosomes and subsequent externalization depend on its binding to phosphoinositides on endosomal membranes. These findings begin to unravel the unconventional mechanism of tTG secretion which utilizes the long loop of endosomal recycling pathway and indicate involvement of endosomal trafficking in non-classical protein secretion.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Evgeny A
authors.initials: EA
authors.lastname: Zemskov
authors.forename: Irina
authors.initials: I
authors.lastname: Mikhailenko
authors.forename: Ru-Ching
authors.initials: RC
authors.lastname: Hsia
authors.forename: Liubov
authors.initials: L
authors.lastname: Zaritskaya
authors.forename: Alexey M
authors.initials: AM
authors.lastname: Belkin
mesh_terms: D000818:Animals; D011992:Endosomes / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010743:Phospholipids / Q000378:metabolism*; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D010743:Phospholipids; D011503:Transglutaminases