The Role of CD9 in Regulating TNF-α-Induced Expression of A Disintegrin and Metalloprotease 17 (ADAM17) in Aortic Endothelial Cells

Abstract

ADAM17 is an inducible metalloprotease that cleaves membrane-anchored proteins

involved in a variety of homeostatic and pathophysiological processes. The mechanisms

responsible for activation and gene expression of ADAM17 are a matter of debate, as

they depend on the cellular context. Here we investigate the role of the tetraspanin, CD9,

in regulating the shedding activity and gene expression of ADAM17 in human aortic

endothelial cells. In contrast to what has been previously reported for other substrates of

ADAM17, we found that a deficiency of CD9 did not increase ADAM17-dependent

shedding of CX3CL1. Instead, knockdown of CD9 resulted in a reduction in immature and

mature ADAM17 protein. This reduction was not caused by an increase in ADAM17

degradation, but rather a decrease in ADAM17 transcription. We found an associated

reduction in constitutive and TNF-α-induced NF-κB activation upon knockdown of CD9,

which may potentially explain the reduction in its downstream target, ADAM17.