A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies

被引:257
作者
Lloyd, DJ
Trembath, RC
Shackleton, S
机构
[1] Univ Leicester, Dept Genet, Div Med Genet, Leicester LE1 7RH, Leics, England
[2] Univ Leicester, Dept Med, Div Med Genet, Leicester LE1 7RH, Leics, England
关键词
D O I
10.1093/hmg/11.7.769
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The gene encoding nuclear lamins A and C is mutated in at least three inherited disorders. Two of these, Emery-Dreifuss muscular dystrophy (EDMD-AD) and a form of dilated cardiomyopathy (CMD1A), involve muscle defects, and the other, familial partial lipodystrophy (FPLD), involves loss of subcutaneous adipose tissue. Mutations causing FPLD, in contrast to those causing muscle disorders, are tightly clustered within the C-terminal domain of lamin A/C. We investigated the expression and subcellular localization of FPLD lamin A mutants and found no abnormalities. We therefore set out to identify proteins interacting with the C-terminal domain of lamin A by screening a mouse 3T3-L1 adipocyte library in a yeast two-hybrid interaction screen. Using this approach, the adipocyte differentiation factor, sterol response element binding protein 1 (SREBP1) was identified as a novel lamin A interactor. In vitro glutathione S-transferase pull-down and in vivo co-immunoprecipitation studies confirmed an interaction between lamin A and both SREBP1a and 1c. A binding site for lamin A was identified in the N-terminal transcription factor domain of SREBP1, between residues 227 and 487. The binding of lamin A to SREBP1 was noticeably reduced by FPLD mutations. Interestingly, one EDMD-AD mutation also interfered with the interaction between lamin A and SREBP1. Whilst the physiological relevance of this interaction has yet to be elucidated, these data raise the intriguing possibility that fat loss seen in laminopathies may be caused, at least in part, by reduced binding of the adipoctye differentiation factor SREBP1 to lamin A.
引用
收藏
页码:769 / 777
页数:9
相关论文
共 50 条
[31]   Nuclear import of sterol regulatory element-binding protein-2, a basic helix-loop-helix-leucine zipper (bHLH-Zip)-containing transcription factor, occurs through the direct interaction of importin β with HLH-Zip [J].
Nagoshi, E ;
Imamoto, N ;
Sato, R ;
Yoneda, Y .
MOLECULAR BIOLOGY OF THE CELL, 1999, 10 (07) :2221-2233
[32]  
Östlund C, 2001, J CELL SCI, V114, P4435
[33]   PTG, a protein phosphatase 1-binding protein with a role in glycogen metabolism [J].
Printen, JA ;
Brady, MJ ;
Saltiel, AR .
SCIENCE, 1997, 275 (5305) :1475-1478
[34]  
Raharjo WH, 2001, J CELL SCI, V114, P4447
[35]   LMNA, encoding lamin A/C, is mutated in partial lipodystrophy [J].
Shackleton, S ;
Lloyd, DJ ;
Jackson, SNJ ;
Evans, R ;
Niermeijer, MF ;
Singh, BM ;
Schmidt, H ;
Brabant, G ;
Kumar, S ;
Durrington, PN ;
Gregory, S ;
O'Rahilly, S ;
Trembath, RC .
NATURE GENETICS, 2000, 24 (02) :153-156
[36]   Major binding sites for the nuclear import receptor are the internal nucleoporin Nup153 and the adjacent nuclear filament protein Tpr [J].
Shah, S ;
Tugendreich, S ;
Forbes, D .
JOURNAL OF CELL BIOLOGY, 1998, 141 (01) :31-49
[37]   Incorporation of the nuclear pore basket protein Nup 153 into nuclear pore structures is dependent upon lamina assembly:: evidence from cell-free extracts of Xenopus eggs [J].
Smythe, C ;
Jenkins, HE ;
Hutchison, CJ .
EMBO JOURNAL, 2000, 19 (15) :3918-3931
[38]   Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C [J].
Speckman, RA ;
Garg, A ;
Du, FH ;
Bennett, L ;
Veile, R ;
Arioglu, E ;
Taylor, SI ;
Lovett, M ;
Bowcock, AM .
AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 66 (04) :1192-1198
[39]   Subnuclear trafficking of estrogen receptor-α and steroid receptor coactivator-1 [J].
Stenoien, DL ;
Mancini, MG ;
Patel, K ;
Allegretto, EA ;
Smith, CL ;
Mancini, MA .
MOLECULAR ENDOCRINOLOGY, 2000, 14 (04) :518-534
[40]   Nuclear lamins: Their structure, assembly, and interactions [J].
Stuurman, N ;
Heins, S ;
Aebi, U .
JOURNAL OF STRUCTURAL BIOLOGY, 1998, 122 (1-2) :42-66