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.
Dominici
S
S
Institute of Biochemistry, University of Urbino, Urbino, Italy.
Fiori
V
V
Magnani
M
M
Schena
E
E
Capanni
C
C
Camozzi
D
D
D'Apice
M R
MR
Le Dour
C
C
Auclair
M
M
Caron
M
M
Novelli
G
G
Vigouroux
C
C
Maraldi
N M
NM
Lattanzi
G
G
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