title: Inhibitors of protein geranylgeranyltransferase-I lead to prelamin A accumulation in cells by inhibiting ZMPSTE24.
abstract: Protein farnesyltransferase (FTase) inhibitors, generally called "FTIs," block the farnesylation of prelamin A, inhibiting the biogenesis of mature lamin A and leading to an accumulation of prelamin A within cells. A recent report found that a GGTI, an inhibitor of protein geranylgeranyltransferase-I (GGTase-I), caused an exaggerated accumulation of prelamin A in the presence of low amounts of an FTI. This finding was interpreted as indicating that prelamin A can be alternately prenylated by GGTase-I and that inhibiting both protein prenyltransferases leads to more prelamin A accumulation than blocking FTase alone. Here, we tested an alternative hypothesis-GGTIs are not specific for GGTase-I, and they lead to prelamin A accumulation by inhibiting ZMPSTE24 (a zinc metalloprotease that converts farnesyl-prelamin A to mature lamin A). In our studies, commonly used GGTIs caused prelamin A accumulation in human fibroblasts, but the prelamin A in GGTI-treated cells exhibited a more rapid electrophoretic mobility than prelamin A from FTI-treated cells. The latter finding suggested that the prelamin A in GGTI-treated cells might be farnesylated (which would be consistent with the notion that GGTIs inhibit ZMPSTE24). Indeed, metabolic labeling studies revealed that the prelamin A in GGTI-treated fibroblasts is farnesylated. Moreover, biochemical assays of ZMPSTE24 activity showed that ZMPSTE24 is potently inhibited by a GGTI. Our studies show that GGTIs inhibit ZMPSTE24, leading to an accumulation of farnesyl-prelamin A. Thus, caution is required when interpreting the effects of GGTIs on prelamin A processing.
authors.affiliation: Department of Medicine and University of California, Los Angeles, CA 90095, USA.
authors.forename: Sandy Y
authors.initials: SY
authors.lastname: Chang
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Hudon-Miller
authors.forename: Shao H
authors.initials: SH
authors.lastname: Yang
authors.forename: Hea-Jin
authors.initials: HJ
authors.lastname: Jung
authors.forename: John M
authors.initials: JM
authors.lastname: Lee
authors.forename: Emily
authors.initials: E
authors.lastname: Farber
authors.forename: Thangaiah
authors.initials: T
authors.lastname: Subramanian
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Andres
authors.forename: H Peter
authors.initials: HP
authors.lastname: Spielmann
authors.forename: Christine A
authors.initials: CA
authors.lastname: Hrycyna
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Loren G
authors.initials: LG
authors.lastname: Fong
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D057786:Peptidomimetics / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism*
chemical_list: D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D057786:Peptidomimetics; D011480:Protease Inhibitors; D011498:Protein Precursors; C090764:prelamin A; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human