Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice.
The mouse ortholog of human FACE-1, Zmpste24, is a multispanning membrane protein widely distributed in mammalian tissues and structurally related to Afc1p/ste24p, a yeast metalloproteinase involved in the maturation of fungal pheromones. Disruption of the gene Zmpste24 caused severe growth retardation and premature death in homozygous-null mice. Histopathological analysis of the mutant mice revealed several abnormalities, including dilated cardiomyopathy, muscular dystrophy and lipodystrophy. These alterations are similar to those developed by mice deficient in A-type lamin, a major component of the nuclear lamina, and phenocopy most defects observed in humans with diverse congenital laminopathies. In agreement with this finding, Zmpste24-null mice are defective in the proteolytic processing of prelamin A. This deficiency in prelamin A maturation leads to the generation of abnormalities in nuclear architecture that probably underlie the many phenotypes observed in both mice and humans with mutations in the lamin A gene. These results indicate that prelamin A is a specific substrate for Zmpste24 and demonstrate the usefulness of genetic approaches for identifying the in vivo substrates of proteolytic enzymes.
Pendás
Alberto M
AM
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
Zhou
Zhongjun
Z
Cadiñanos
Juan
J
Freije
José M P
JM
Wang
Jianming
J
Hultenby
Kjell
K
Astudillo
Aurora
A
Wernerson
Annika
A
Rodríguez
Francisco
F
Tryggvason
Karl
K
López-Otín
Carlos
C
D017667:Adipocytes / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002467:Cell Nucleus / Q000473:pathology; D005260:Female; D006801:Humans; D034904:Lamin Type A; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D008666:Metalloendopeptidases / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009132:Muscles / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D011498:Protein Precursors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse