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J Biol Chem, Vol. 274, Issue 10, 6536-6545, March 5, 1999

Cellular Localization and Role of Prohormone Convertases in the Processing of Pro-melanin Concentrating Hormone in Mammals

Agnès Viale, Christine Ortola, Guillaume Hervieu, Machi Furuta^**, Pierre Barbero, Donald F. Steiner^**, Nabil G. Seidah^§§, and Jean-Louis Nahon

From the  Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UPR411, 660 route des Lucioles, Sophia-Antipolis, 06560 Valbonne, France, the  Department of Biochemistry and Molecular Biology and the ^** Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637, and the ^§§ Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada

Melanin concentrating hormone (MCH) and neuropeptide EI (NEI) are two peptides produced from the same precursor in mammals, by cleavage at the Arg¹⁴⁵-Arg¹⁴⁶ site and the Lys¹²⁹-Arg¹³⁰ site, respectively. We performed co-localization studies to reveal simultaneously the expression of MCH mRNA and proconvertases (PCs) such as PC1/3 or PC2. In the rat hypothalamus, PC2 was present in all MCH neurons, and PC1/3 was present in about 15-20% of these cells. PC1/3 or PC2 was not found in MCH-positive cells in the spleen. In GH₄C₁ cells co-infected with vaccinia virus (VV):pro-MCH along with VV:furin, PACE4, PC1/3, PC2, PC5/6A, PC5/6B, or PC7, we observed only efficient cleavage at the Arg¹⁴⁵-Arg¹⁴⁶ site to generate mature MCH. Co-expression of pro-MCH together with PC2 and 7B2 resulted in very weak processing to NEI. Comparison of pro-MCH processing patterns in PC1/3- or PC2-transfected PC12 cells showed that PC2 but not PC1/3 generated NEI. Finally, we analyzed the pattern of pro-MCH processing in PC2 null mice. In the brain of homozygotic mutants, the production of mature NEI was dramatically reduced. In contrast, MCH content was increased in the hypothalamus of PC2 null mice. In the spleen, a single large MCH-containing peptide was identified in both wild type and PC2 null mice. Together, our data suggest that pro-MCH is processed differently in the brain and in peripheral organs of mammals. PC2 is the key enzyme that produces NEI, whereas several PCs may cleave at the Arg¹⁴⁵-Arg¹⁴⁶ site to generate MCH in neuronal cell types.

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