Lamins structurally support the nuclear membrane and influence various nuclear,
intracellular and extracellular processes. Hutchinson-Gilford progeria syndrome
(HGPS), a premature aging syndrome, is caused by mutation in LMNA encoding
lamin A and lamin C. Lamin A is synthesized as a precursor, prelamin A, whose
carboxyl-terminus undergoes farnesylation and other modifications before being
cleaved off by zinc metallopeptidase STE24 homolog (ZMPSTE24). A prelamin A
variant (termed progerin) lacking a 50-amino acid fragment containing the cleavage
site is expressed in cells of patients with HGPS. Therefore, farnesylated progerin
accumulates at the inner nuclear membrane. Farnesylated prelamin A (with a single
amino acid change) also accumulates in cells from a patient with a progeroid
disorder (PD) carrying an LMNA point mutation disrupting the ZMPSTE24 cleavage
site. Likewise, mutations in ZMPSTE24 leading to partial loss of proteolytic activity
result in prelamin A accumulation in mandibuloacral dysplasia type B (MDB). The PD
and MDB patients have phenotypes overlapping with but less severe than HGPS.
Hence, the accumulation of prelamin A may not lead to exactly the same cellular
defects observed in HGPS. Previously we showed that nesprin-2 and SUN2-
dependent nuclear movement and centrosome orientation (“cell polarity”) in
migratory fibroblasts were inhibited by progerin due to elevated association
between the nucleus and microtubules. Here we find that the diffusional mobilities
of nesprin-2G and SUN2 are affected by the accumulation of prelamin A in
fibroblasts from the PD and MDB patients, but only fibroblasts from those with MDB
exhibit a cell polarity defect. Cell polarity is also impaired in embryonic fibroblasts
from Zmpste24-null mice and NIH3T3 cells depleted of ZMPSTE24 using siRNAs. Cell
polarity defects in these cells could be rescued by inhibiting protein farnesylation.
As in HGPS fibroblasts, these defects can also be rescued by inhibiting dynein. These
results show that farnesylated prelamin A and progerin similarly affect fibroblast
polarization.