Direct Synthesis of Lamin A, Bypassing Prelamin A Processing, Causes Misshapen Nuclei in Fibroblasts but No Detectable Pathology in Mice

Catherine Coffinier; Hea-Jin Jung; Ziwei Li; Chika Nobumori; Ui Jeong Yun; Emily A Farber; Brandon S Davies; Michael M Weinstein; Shao H Yang; Jan Lammerding; Javad N Farahani; Laurent A Bentolila; Loren G Fong; Stephen G Young

doi:10.1074/jbc.M110.128835

Back

Direct Synthesis of Lamin A, Bypassing Prelamin A Processing, Causes Misshapen Nuclei in Fibroblasts but No Detectable Pathology in Mice

Journal article

Open access

Peer reviewed

Direct Synthesis of Lamin A, Bypassing Prelamin A Processing, Causes Misshapen Nuclei in Fibroblasts but No Detectable Pathology in Mice

Catherine Coffinier, Hea-Jin Jung, Ziwei Li, Chika Nobumori, Ui Jeong Yun, Emily A Farber, Brandon S Davies, Michael M Weinstein, Shao H Yang, Jan Lammerding, …

The Journal of biological chemistry, Vol.285(27), pp.20818-20826

07/02/2010

DOI: 10.1074/jbc.M110.128835

PMCID: PMC2898298

PMID: 20439468

Files and links (1)

url

https://doi.org/10.1074/jbc.M110.128835View

Published (Version of record) Open Access

Abstract

Lamin A, a key component of the nuclear lamina, is generated from prelamin A by four post-translational processing steps: farnesylation, endoproteolytic release of the last three amino acids of the protein, methylation of the C-terminal farnesylcysteine, and finally, endoproteolytic release of the last 15 amino acids of the protein (including the farnesylcysteine methyl ester). The last cleavage step, mediated by ZMPSTE24, releases mature lamin A. This processing scheme has been conserved through vertebrate evolution and is widely assumed to be crucial for targeting lamin A to the nuclear envelope. However, its physiologic importance has never been tested. To address this issue, we created mice with a “mature lamin A-only” allele ( Lmna LAO ), which contains a stop codon immediately after the last codon of mature lamin A. Thus, Lmna LAO/LAO mice synthesize mature lamin A directly, bypassing prelamin A synthesis and processing. The levels of mature lamin A in Lmna LAO/LAO mice were indistinguishable from those in “prelamin A-only” mice ( Lmna PLAO/PLAO ), where all of the lamin A is produced from prelamin A. Lmna LAO/LAO exhibited normal body weights and had no detectable disease phenotypes. A higher frequency of nuclear blebs was observed in Lmna LAO/LAO embryonic fibroblasts; however, the mature lamin A in the tissues of Lmna LAO/LAO mice was positioned normally at the nuclear rim. We conclude that prelamin A processing is dispensable in mice and that direct synthesis of mature lamin A has little if any effect on the targeting of lamin A to the nuclear rim in mouse tissues.

Prelamin A

Nucleus

Genetic Diseases

Mouse Genetics

Gene Knockin

Protein Processing

Protein Farnesylation

Nuclear Lamina

Cell Biology

Lamin A

Details

Title: Subtitle: Direct Synthesis of Lamin A, Bypassing Prelamin A Processing, Causes Misshapen Nuclei in Fibroblasts but No Detectable Pathology in Mice
Creators: Catherine Coffinier - From the
Hea-Jin Jung - From the
Ziwei Li - From the
Chika Nobumori - From the
Ui Jeong Yun - From the
Emily A Farber - From the
Brandon S Davies - From the
Michael M Weinstein - From the
Shao H Yang - From the
Jan Lammerding - the
Javad N Farahani - California NanoSystems Institute, University of California, Los Angeles, California 90095 and
Laurent A Bentolila - Department of Chemistry and Biochemistry, and
Loren G Fong - From the
Stephen G Young - From the
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.285(27), pp.20818-20826
DOI: 10.1074/jbc.M110.128835
PMID: 20439468
PMCID: PMC2898298
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
Grant note: AG035626; HL76839; HL86683; GM66152; HL082792; NS059348; 44385-WS-29646 / National Institutes of Health
Language: English
Date published: 07/02/2010
Academic Unit: Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology
Record Identifier: 9984025251202771

Direct Synthesis of Lamin A, Bypassing Prelamin A Processing, Causes Misshapen Nuclei in Fibroblasts but No Detectable Pathology in Mice

Files and links (1)

Abstract

Details

Metrics