Role of prodomain in importin-mediated nuclear localization and activation of caspase-2

Belinda C. Baliga, Paul A. Colussi, Stuart H. Read, Manisha M. Dias, David A. Jans, Sharad Kumar

Research output: Contribution to journalArticleResearchpeer-review

85 Citations (Scopus)

Abstract

Caspase-2 is unique among mammalian caspases because it localizes to the nucleus in a prodomain-dependent manner. The caspase-2 prodomain also regulates caspase-2 activity via a caspase recruitment domain that mediates oligomerization of procaspase-2 molecules and their subsequent autoactivation. In this study we sought to map specific functional regions in the caspase-2 prodomain that regulate its nuclear transport and also its activation. Our data indicate that caspase-2 contains a classical nuclear localization signal (NLS) at the C terminus of the prodomain which is recognized by the importin α/β heterodimer. The mutation of a conserved Lys residue in the NLS abolishes nuclear localization of caspase-2 and binding to the importin α/β heterodimer. Although caspase-2 is imported into the nucleus, mutants lacking the NLS were still capable of inducing apoptosis upon overexpression in transfected cells. We define a region in the prodomain that regulates the ability of caspase-2 to form dot- and filament-like structures when ectopically expressed, which in turn promotes cell killing. Our data provides a mechanism for caspase-2 nuclear import and demonstrate that association of procaspase-2 into higher order structures, rather than its nuclear localization, is required for caspase-2 activation and its ability to induce apoptosis.

Original languageEnglish
Pages (from-to)4899-4905
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number7
DOIs
Publication statusPublished - 14 Feb 2003

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