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J. Biol. Chem., Vol. 281, Issue 19, 13150-13158, May 12, 2006

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Tid1 Isoforms Are Mitochondrial DnaJ-like Chaperones with Unique Carboxyl Termini That Determine Cytosolic Fate^*

Bin Lu, Nuria Garrido¹, Johannes N. Spelbrink, and Carolyn K. Suzuki²

From the University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Department of Biochemistry and Molecular Biology, Newark, New Jersey 07103 and Institute of Medical Technology and Tampere University Hospital, University of Tampere, FIN-33014 Tampere, Finland

Tid1 is a human homolog of bacterial DnaJ and the Drosophila tumor suppressor Tid56 that has two alternatively spliced isoforms, Tid1-long and -short (Tid1-L and -S), which differ only at their carboxyl termini. Although Tid1 proteins localize overwhelmingly to mitochondria, published data demonstrate principally nonmitochondrial protein interactions and activities. This study was undertaken to determine whether Tid1 proteins function as mitochondrial DnaJ-like chaperones and to resolve the paradox of how proteins targeted primarily to mitochondria function in nonmitochondrial pathways. Here we demonstrate that Tid1 isoforms exhibit a conserved mitochondrial DnaJ-like function substituting for the yeast mitochondrial DnaJ-like protein Mdj1p. Like Mdj1p, Tid1 localizes to human mitochondrial nucleoids, which are large protein complexes bound to mitochondrial DNA. Unlike other DnaJs, Tid1-L and -S form heterocomplexes; both unassembled and complexed Tid1 are observed in human cells. Results demonstrate that Tid1-L has a longer residency time in the cytosol prior to mitochondrial import as compared with Tid1-S; Tid1-L is also significantly more stable in the cytosol than Tid1-S, which is rapidly degraded. The longer cytosolic residency time and the half-life of Tid1-L are explained by its interaction with cytosolic Hsc70 and potential protein substrates such as the STAT1 and STAT3 transcription factors. We show that the unique carboxyl terminus of Tid1-L is required for interaction with Hsc70 and STAT1 and -3. We propose that the association of Tid1 with chaperones and/or protein substrates in the cytosol provides a mechanism for the alternate fates and functions of Tid1 in mitochondrial and nonmitochondrial pathways.

Received for publication, August 19, 2005 , and in revised form, March 7, 2006.

^* This work was supported in part by grants from the National Institutes of Health, the Foundation of the University of Medicine and Dentistry of New Jersey-New Jersey Medical School (to C. K. S.), from the Academy of Finland, the Centre of Excellence Program, and the Medical Fund of Tampere University Hospital (to J. N. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4.

¹ Present address: Dept. de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Miguel Servet 177, 50013, Zaragoza, Spain.

² To whom correspondence should be addressed: UMDNJ-New Jersey Medical School, Dept. of Biochemistry and Molecular Biology, 185 South Orange Ave., Newark, NJ 07103. Tel.: 973-972-1555; Fax: 973-972-5594; E-mail: suzukick{at}umdnj.edu.

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