TLR ligand-induced podosome disassembly in dendritic cells is ADAM17 dependent.
Toll-like receptor (TLR) signaling induces a rapid reorganization of the actin cytoskeleton in cultured mouse dendritic cells (DC), leading to enhanced antigen endocytosis and a concomitant loss of filamentous actin-rich podosomes. We show that as podosomes are lost, TLR signaling induces prominent focal contacts and a transient reduction in DC migratory capacity in vitro. We further show that podosomes in mouse DC are foci of pronounced gelatinase activity, dependent on the enzyme membrane type I matrix metalloprotease (MT1-MMP), and that DC transiently lose the ability to degrade the extracellular matrix after TLR signaling. Surprisingly, MMP inhibitors block TLR signaling-induced podosome disassembly, although stimulated endocytosis is unaffected, which demonstrates that the two phenomena are not obligatorily coupled. Podosome disassembly caused by TLR signaling occurs normally in DC lacking MT1-MMP, and instead requires the tumor necrosis factor alpha-converting enzyme ADAM17 (a disintegrin and metalloprotease 17), which demonstrates a novel role for this "sheddase" in regulating an actin-based structure.
West
Michele A
MA
Division of Cell Biology and Immunology, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Prescott
Alan R
AR
Chan
Kui Ming
KM
Zhou
Zhongjun
Z
Rose-John
Stefan
S
Scheller
Jürgen
J
Watts
Colin
C