Unaltered cleavage and secretion of angiotensin-converting enzyme in tumornecrosis factor-alpha-converting enzyme-deficient mice

Mammalian angiotensin-converting enzyme (ACE) is one of several biologicall y important ectoproteins that exist in both membrane-bound and soluble form s as a result of a post-translational proteolytic cleavage. It has been sug gested that a common proteolytic system is responsible for the cleavage of a diverse group of membrane ectoproteins, and tumor necrosis factor-alpha-c onverting enzyme (TACE), a recently purified disintegrin-metalloprotease, h as been implicated in the proteolytic cleavage of several cell surface prot eins. Mice devoid of TACE have been developed by gene targeting. Such mice could provide a useful system to determine if TACE is responsible for the c leavage of other ectoproteins, Cultured fibroblasts without TACE activity, when transfected with cDNA encoding for the testicular isozyme of ACE (ACE( T)), synthesized and secreted ACE(T) normally after a proteolytic cleavage near the C terminus. In addition, similar quantities of the soluble, C-term inally truncated somatic isozyme of ACE (ACE(P)) were present in the serum of wild-type and TACE-deficient mice. These results demonstrate that TACE i s not essential in the generation of soluble ACE under physiological condit ions. Finally, we also report solubilization of ACE-secretase, the enzyme t hat cleaves ACE, from mouse ACE89 cells and from rabbit lung. We demonstrat e that soluble ACE-secretase from both sources failed to cleave its substra te in solution, suggesting a requirement for anchoring to the membrane.