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A Plasminogen-Like Protease in Thyroid Rough Microsomes Degrades Thyroperoxidase and Thyroglobulin

Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 476 (A.G.) and Institut National de la Santé et de la Recherche Médicale Unité 555 (P.-J.L., J.B., B.M.), Faculté de Médecine, 13385 Marseille, France

Address all correspondence and requests for reprints to: Bernard Mallet, Laboratoire de Biochimie, Faculté de Médecine, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France. E-mail: bernard.mallet{at}medecine.univ-mrs.fr.

Proteasome activity takes place in the cytosolic compartment and acts to degrade several proteins translated and unfolded. In transfected CHO cells expressing thyroid peroxidase (TPO), just-translated TPO undergoes proteasome activity, and then a second proteolytic system degrades more mature forms of TPO. A plasminogen-like (Pl-like) protease is found in microsomal liver membranes and in the thyroid. In the thyroid, this Pl-like protease is localized in the follicular lumen and efficiently degrades thyroglobulin (Tg) in vitro. Here we checked for the presence, in purified endoplasmic reticulum (ER) membranes of transfected CHO and in rough microsomes purified from thyroid tissue, of a second proteolytic system, different from the proteasome, and active against the two major proteins of the thyroid gland, TPO and Tg. We first confirmed that this proteolytic system was able to degrade folded endogenous TPO. We showed also that externally added TPO (folded form) was degraded by opened vesicles of ER in the same system. For thyroid tissue, we showed that added TPO, as well as purified Tg, was degraded by some unknown membrane-associated protease(s) in human and porcine thyroid rough microsomes, whereas BSA and IgG were not. These results indicated that major thyroid glycoproteins are preferential substrates of such protease(s). Immunoblot and zymography experiments identified the unknown membrane-associated protease in rough microsomes from thyroid tissues as being a Pl-like protease. These results highly suggest that this system acts as a nonproteasomal degradation enzyme at the ER level, and we hypothesize that it contributes in regulating the level of major thyroid glycoproteins.