Peiretti Franck, Canault Matthias, Morange Pierre, Alessi Marie-Christine, Nalbone Gilles
Inserm U626, Faculté de Médecine, 27, boulevard Jean Moulin, 13385 Marseille Cedex 5, France.
Med Sci (Paris). 2009 Jan;25(1):45-50. doi: 10.1051/medsci/200925145.
ADAM17 was initially characterized as the TNF Alpha Converting Enzyme (TACE) and, until now, has been the most studied member of the ADAM family. It is a type I transmembrane metalloproteinase involved in the shedding of the extracellular domain of several transmembrane proteins (at least 40) such as cytokines, growth factors, receptors or adhesion molecules. As a consequence, depending on the transmembrane molecule cleaved, one may expect possible opposite effects of ADAM17 activity on inflammation (e.g. TNF and its receptors). The role of ADAM17 in regulating inflammatory cellular processes is clearly demonstrated in cells deficient in active ADAM17 or expressing substrates mutated for the ADAM17 cleavage site. As ADAM17-deficient mice died at birth, mice overexpressing the mutated uncleavable form of some substrates and recently conditional knock-out of ADAM17 are used to approach in vivo the role of this metalloprotease in regulating inflammation. Arguments are provided that ADAM17 plays a role in atherosclerosis, in adipose tissue metabolism, insulin resistance and diabetes. The multitude of substrates cleaved by ADAM17 makes this enzyme an attractive candidate to study its role in inflammation-driven pathologies.
ADAM17最初被鉴定为肿瘤坏死因子α转换酶（TACE），到目前为止，它一直是ADAM家族中研究最多的成员。它是一种I型跨膜金属蛋白酶，参与多种跨膜蛋白（至少40种）胞外结构域的脱落，这些跨膜蛋白包括细胞因子、生长因子、受体或黏附分子。因此，根据被切割的跨膜分子不同，人们可能预期ADAM17活性对炎症（如肿瘤坏死因子及其受体）会产生相反的影响。在缺乏活性ADAM17或表达ADAM17切割位点突变底物的细胞中，ADAM17在调节炎症细胞过程中的作用得到了明确证实。由于ADAM17基因缺陷的小鼠在出生时就死亡，因此，过表达某些底物的不可切割突变形式的小鼠以及最近通过条件性敲除ADAM17的小鼠被用于在体内研究这种金属蛋白酶在调节炎症中的作用。有证据表明，ADAM17在动脉粥样硬化、脂肪组织代谢、胰岛素抵抗和糖尿病中发挥作用。ADAM17切割的底物众多，这使得该酶成为研究其在炎症驱动的病理过程中作用的一个有吸引力的候选对象。
