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PNAS 98 (18): 10148-10153

Copyright © 2001 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

Caspase cleavage of MST1 promotes nuclear translocation and chromatin condensation

Seiji Ura*, Norihisa Masuyama*, Jonathan D. Graves{dagger}, and Yukiko Gotoh*,{ddagger},§

*Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; {dagger}Department of Immunology, University of Washington Medical Center, Seattle, WA 98195; and {ddagger}PRESTO Research Project, Japan Science and Technology Corporation, Osaka, 560-0082 Japan

Received for publication April 4, 2001.

Abstract: MST1, mammalian STE20-like kinase 1, is a serine/threonine kinase that is cleaved and activated by caspases during apoptosis. MST1 is capable of inducing apoptotic morphological changes such as chromatin condensation upon overexpression. In this study, we show that MST1 contains two functional nuclear export signals (NESs) in the C-terminal domain, which is released from the N-terminal kinase domain upon caspase-mediated cleavage. Full-length MST1 is excluded from the nucleus and localized to the cytoplasm. However, either truncation of the C-terminal domain, point mutation of the two putative NESs, or treatment with leptomycin B, an inhibitor of the NES receptor, results in nuclear localization of MST1. Staurosporine treatment induces chromatin condensation, MST1 cleavage, and nuclear translocation. Staurosporine-induced chromatin condensation is partially inhibited by expressing a kinase-negative mutant of MST1, suggesting an important role of MST1 in this process. Significantly, MST1 is more efficient at inducing chromatin condensation when it is constitutively localized to the nucleus by mutation of its NESs. Moreover, inhibition of MST1 nuclear translocation by mutation of its cleavage sites reduces its ability to induce chromatin condensation. Taken together, these results suggest that truncation of the C-terminal domain of MST1 by caspases may result in translocation of MST1 into the nucleus, where it promotes chromatin condensation.

§ To whom reprint requests should be addressed. E-mail: ygotoh{at}iam.u-tokyo.ac.jp.

Edited by Hidesaburo Hanafusa, Osaka Bioscience Institute, Osaka, Japan, and approved June 22, 2001

This paper was submitted directly (Track II) to the PNAS office.

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