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J. Biol. Chem., Vol. 279, Issue 52, 54783-54792, December 24, 2004

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Tissue Transglutaminase Is a Multifunctional BH3-only Protein^*

Carlo Rodolfo, Elisabetta Mormone, Paola Matarrese, Fabiola Ciccosanti¶, Maria Grazia Farrace, Elvira Garofano, Lucia Piredda, Gian Maria Fimia¶, Walter Malorni, and Mauro Piacentini||

From the Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy, the Department of Drug Research and Evaluation, Section of Cell Aging and Degeneration, Istituto Superiore di Sanità, 00161 Rome, Italy, and the ^¶Laboratory of Cell Biology and E.M., INMI-IRCCS Lazzaro Spallanzani, 00149 Rome, Italy

Tissue transglutaminase (TG2) protein accumulates to high levels in cells during early stages of apoptosis both in vivo and in vitro. The analysis of the TG2 primary sequence showed the presence of an eight amino acid domain, sharing 70% identity with the Bcl-2 family BH3 domain. Cell-permeable peptides, mimicking the domain sequence, were able to induce Bax conformational change and translocation to mitochondria, mitochondrial depolarization, release of cytochrome c, and cell death. Moreover, we found that the TG2-BH3 peptides as well as TG2 itself were able to interact with the pro-apoptotic Bcl-2 family member Bax, but not with anti-apoptotic members Bcl-2 and Bcl-X_L. Mutants in the TG2-BH3 domain failed to sensitize cells toward apoptosis. In TG2-overexpressing cells about half of the protein is localized on the outer mitochondrial membrane where, upon cell death induction, it cross-links many protein substrates including Bax. TG2 is the first member of a new subgroup of multifunctional BH3-only proteins showing a large mass size (80 kDa) and enzymatic activity.

Received for publication, September 23, 2004 , and in revised form, October 12, 2004.

The authors would like to dedicate this article to Prof. Francesco Autuori on the occasion of his 71st birthday.

^* This work was supported in part by Grants QLG1-CT-1999-00739 and QLK3-CT-2002-02017 from the European Community, PRIN-2002 and FIRB-2001 from Ministero dell'Istruzione, dell'Università e della Roma, Ricerca Corrente e Finalizzata from the Ministry of Health and Associazione Italiana per la Ricerca sul Cancro. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: University of Rome Tor Vergata, Dept. of Biology, Via della Ricerca Scientifica, 00133 Rome, Italy. Tel.: 390672594234; Fax: 39062023500; E-mail: mauro.piacentini{at}uniroma2.it.

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