Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase–deficient mice
Abstract
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.
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Zmpste24 − /− mice exhibit elevated expression of caspase 1 and Nlrp3, severe growth retardation, dilated cardiomyopathy, muscular dystrophy, lipodystrophy and premature death.
“In addition, two independently generated mouse models deficient in the Zmpste24 gene (Zmpste24 − /− mice) also exhibit elevated expression of caspase 1 and Nlrp3, severe growth retardation, dilated cardiomyopathy, muscular dystrophy, lipodystrophy and premature death.307,308”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [308]
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- Authors
- Pendás, A. M., Zhou, Z., Cadiñanos, J., Freije, J. M. P., Wang, J., Hultenby, K., Astudillo, A., Wernerson, A., Rodríguez, F., Tryggvason, K., & López-Otín, C.
- Affiliations
- Universidad de Oviedo (ES)
- Karolinska Institutet (SE)
- Hospital Universitario Central de Asturias (ES)
- ORCID
- Venue
- Nature Genetics
- Published
- 2002-04-01
- Volume
- 31
- Issue
- 1
- Pages
- 94-99
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2036973053
- Cited by
- 554
- References
- 19
- Citations by year
- 2026: 15 · 2025: 8 · 2024: 13 · 2023: 23 · 2022: 17 · 2021: 15 · 2020: 19 · 2019: 25 · 2018: 35 · 2017: 21 · 2016: 20 · 2015: 17 · 2014: 20 · 2013: 34 · 2012: 25
- FWCI
- 7.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- Swedish Cancer Foundation
- European Commission
- Eusko Jaurlaritza
- Karolinska Institutet
- Novo Nordisk
- Comisión Interministerial de Ciencia y Tecnología
- Novo Nordisk Fonden
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- ZMPSTE24, lamin A, laminopathies, metalloproteinases, nuclear lamina, dilated cardiomyopathy, muscular dystrophy, lipodystrophy, nuclear organization, growth retardation, substrate identification
- MeSH terms
- Animals, Cell Nucleus, Female, Humans, Male, Membrane Proteins, Metalloendopeptidases, Mice, Inbred C57BL, Muscles, Myocardium, Nuclear Proteins, Phenotype, Protein Precursors, Protein Processing, Post-Translational, Adipocytes, Mice, Knockout, Lamin Type A, Mice
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