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MBC in Press, published online ahead of print October 15, 2008
Mol. Biol. Cell 10.1091/mbc.E08-07-0704

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Submitted on July 10, 2008
Revised on September 26, 2008
Accepted on October 2, 2008

Analysis of Prelamin a Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment

Jemima Barrowman, Corinne Hamblet, Carolyn M. George, and Susan Michaelis

Department of Cell Biology, The Johns Hopkins School of Medicine, Baltimore, MD 21205

Monitoring Editor: Susan R. Wente

Proteins establish and maintain a distinct intracellular localization by means of targeting, retention, and retrieval signals, ensuring most proteins reside predominantly in one cellular location. The enzymes involved in the maturation of lamin A present a challenge to this paradigm. Lamin A is first synthesized as a 74 kDa precursor, prelamin A, with a C-terminal CaaX motif and undergoes a series of post-translational modifications including CaaX processing (farnesylation, aaX cleavage and carboxylmethylation), followed by endoproteolytic cleavage by Zmpste24. Failure to cleave prelamin A results in progeria and related premature aging disorders. Evidence suggests prelamin A is imported directly into the nucleus where it is processed. Paradoxically, the processing enzymes have been shown to reside in the cytosol (farnesyltransferase), or are ER membrane proteins (Zmpste24, Rce1, Icmt) with their active sites facing the cytosol. Here we have reexamined the cellular site of prelamin A processing, and show that the mammalian and yeast processing enzymes Zmpste24 and Icmt exhibit a dual localization to the inner nuclear membrane, as well as the ER membrane. Our findings reveal the nucleus to be a physiologically relevant location for CaaX processing, and provide insight into the biology of a protein at the center of devastating progeroid diseases.

Address correspondence to: Susan Michaelis (michaelis{at}jhmi.edu)






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