Different prelamin A forms accumulate in human fibroblasts: a study in experimental models and progeria.
Lamin A is a component of the nuclear lamina mutated in a group of human inherited disorders known as laminopathies. Among laminopathies, progeroid syndromes and lipodystrophies feature accumulation of prelamin A, the precursor protein which, in normal cells, undergoes a multi-step processing to yield mature lamin A. It is of utmost importance to characterize the prelamin A form accumulated in each laminopathy, since existing evidence shows that drugs acting on protein processing can improve some pathological aspects.We report that two antibodies raised against differently modified prelamin A peptides show a clear specificity to full-length prelamin A or carboxymethylated farnesylated prelamin A, respectively. Using these antibodies, we demonstrated that inhibition of the prelamin A endoprotease ZMPSTE24 mostly elicits accumulation of full-length prelamin A in its farnesylated form, while loss of the prelamin A cleavage site causes accumulation of carboxymethylated prelamin A in progeria cells. These results suggest a major role of ZMPSTE24 in the first prelamin A cleavage step.
Institute of Biochemistry, University of Urbino, Urbino, Italy.
S
S
Dominici
V
V
Fiori
M
M
Magnani
E
E
Schena
C
C
Capanni
D
D
Camozzi
M R
MR
D'Apice
C
C
Le Dour
M
M
Auclair
M
M
Caron
G
G
Novelli
C
C
Vigouroux
N M
NM
Maraldi
G
G
Lattanzi
D000595:Amino Acid Sequence; D000818:Animals; D010450:Endopeptidases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D011371:Progeria / Q000378:metabolism* / Q000473:pathology; D011498:Protein Precursors / Q000378:metabolism*; D017368:Protein Prenylation; D011817:Rabbits / Q000276:immunology
D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D010450:Endopeptidases; C104823:prelamin A endoprotease; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human