Pre-Lamin A processing is linked to heterochromatin organization.
Pre-lamin A undergoes subsequent steps of post-translational modification at its C-terminus, including farnesylation, methylation, and cleavage by ZMPSTE24 metalloprotease. Here, we show that accumulation of different intermediates of pre-lamin A processing in nuclei, induced by expression of mutated pre-lamin A, differentially affected chromatin organization in human fibroblasts. Unprocessed (non-farnesylated) pre-lamin A accumulated in intranuclear foci, caused the redistribution of LAP2alpha and of the heterochromatin markers HP1alpha and trimethyl-K9-histone 3, and triggered heterochromatin localization in the nuclear interior. In contrast, the farnesylated and carboxymethylated lamin A precursor accumulated at the nuclear periphery and caused loss of heterochromatin markers and Lap2alpha in enlarged nuclei. Interestingly, pre-lamin A bound both HP1alpha and LAP2alpha in vivo, but the farnesylated form showed reduced affinity for HP1alpha. Our data show a link between pre-lamin A processing and heterochromatin remodeling and have major implications for understanding molecular mechanisms of human diseases linked to mutations in lamins.
Lattanzi
Giovanna
G
IGM, CNR, Unit of Bologna, c/o IOR, Bologna, Italy. lattanzi@jolly.bo.cnr.it
Columbaro
Marta
M
Mattioli
Elisabetta
E
Cenni
Vittoria
V
Camozzi
Daria
D
Wehnert
Manfred
M
Santi
Spartaco
S
Riccio
Massimo
M
Del Coco
Rosalba
R
Maraldi
Nadir M
NM
Squarzoni
Stefano
S
Foisner
Roland
R
Capanni
Cristina
C
D001707:Biopsy, Needle; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000648:ultrastructure; D062109:Dermatologic Surgical Procedures; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D019084:Fluorescent Antibody Technique, Indirect; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D034904:Lamin Type A; D008565:Membrane Proteins / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D011233:Precipitin Tests; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D011499:Protein Processing, Post-Translational; D012867:Skin / Q000166:cytology; D014162:Transfection
C000715594:CBX5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006570:Heterochromatin; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C093413:lamina-associated polypeptide 2; C090764:prelamin A; D000090266:Chromobox Protein Homolog 5