The role of tetraspanins in the regulation of the A Disintegrin and Metalloprotease 10 (ADAM10)

The A Disintegrin and Metalloprotease 10 (ADAM10) is responsible for the ectodomain shedding of multiple cell surface proteins and is involved in important physiological processes in the brain and other organs. As the responsible -secretase of the amyloid precursor protein (APP), ADAM10 counteracts amyloid-beta liberation, which is the main component of amyloid plaques in Alzheimer’s Disease patients. Tetraspanins were identified as potent regulators of ADAM10 activity. In particular, members of the TspanC8 subgroup of tetraspanins promote ADAM10 maturation and surface trafficking. In the present work, the function of tetraspanin-3 (Tspan3) as a novel ADAM10 interaction partner was characterised. In murine tissues, Tspan3 was detected in almost all tissues and was highly expressed in the brain. Interestingly, Tspan3 expression was enhanced in the brains of Alzheimer’s Disease patients. In cells, Tspan3 was mainly detected in endosomal-lysosomal compartments. Co-immunoprecipitation experiments confirmed Tspan3 as an ADAM10 interaction partner and additionally revealed its interaction with APP and presenilin-1, which is the catalytic active subunit of the -secretase complex. Overexpression of Tspan3 in cells promotes ADAM10-mediated APP processing, without affecting ADAM10 maturation or trafficking to the cell surface. Decreasing Tspan3 internalisation by mutation of a cytosolic endocytic sorting motif increased the surface levels of its partner proteins APP and ADAM10. In contrast to overexpression, downregulation of Tspan3 expression did not alter APP proteolytic processing in cells and mice. Further analysis revealed increased levels of Tspan7 and Tspan5 transcripts in Tspan3-deficient brains, which possibly compensate for the loss of Tspan3 […]