The p.R482W substitution in A-type lamins deregulates SREBP1 activity in Dunnigan-type familial partial lipodystrophy.

Abstract

Nuclear lamins are involved in many cellular functions due to their ability to bind numerous partners including chromatin and transcription factors, and affect their properties. Dunnigan type familial partial lipodystrophy (FPLD2; OMIM#151660) is caused in most cases by the A-type lamin R482W mutation. We report here that the R482W mutation affects the regulatory activity of sterol response element binding protein 1 (SREBP1), a transcription factor that regulates hundreds of genes involved in lipid metabolism and adipocyte differentiation. Using in situ proximity ligation assays (PLA), reporter assays and biochemical and transcriptomic approaches, we show that interactions of SREBP1 with lamin A and lamin C occur at the nuclear periphery and in the nucleoplasm. These interactions involve the Ig-fold of A-type lamins and are favored upon SREBP1 binding to its DNA target sequences. We show that SREBP1, LMNA and sterol response DNA elements form ternary complexes in vitro. In addition, overexpression of A-type lamins reduces transcriptional activity of SREBP1. In contrast, both overexpression of LMNA R482W in primary human preadipocytes and endogenous expression of A-type lamins R482W in FPLD2 patient fibroblasts, reduce A-type lamins-SREBP1 in situ interactions and upregulate a large number of SREBP1 target genes. As this LMNA mutant was previously shown to inhibit adipogenic differentiation, we propose that deregulation of SREBP1 by mutated A-type lamins constitutes one underlying mechanism of the physiopathology of FPLD2. Our data suggest that SREBP1 targeting molecules could be considered in a therapeutic context.

• Authors: Nathalie Vadrot, Isabelle Duband-Goulet, Eva Cabet, Wikayatou Attanda, Alice Barateau, Patrick Vicart, Fabien Gerbal, Nolwenn Briand, Corinne Vigouroux, Anja R Oldenburg, Eivind G Lund, Philippe Collas, Brigitte Buendia
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 7 Pg. 2096-109 (Apr 01 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25524705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Lamin Type A
• SREBF1 protein, human
• Sterol Regulatory Element Binding Protein 1

Topics

• Adult
• Amino Acid Substitution
• Female
• Humans
• Lamin Type A (genetics, metabolism)
• Lipodystrophy, Familial Partial (genetics, metabolism)
• Male
• Middle Aged
• Mutation, Missense
• Protein Binding
• Sterol Regulatory Element Binding Protein 1 (genetics, metabolism)
• Young Adult