Tid1 isoforms are mitochondrial DnaJ-like chaperones with unique carboxyl termini that determine cytosolic fate
Tid1 isoforms are mitochondrial DnaJ-like chaperones with unique carboxyl termini that determine cytosolic fate
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DOI：
10.1074/jbc.m509179200
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发表时间：
2006-05-12
影响因子：
4.8
通讯作者：
Suzuki, CK
中科院分区：
文献类型：
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作者：
Lu, B;Garrido, N;Suzuki, CK
Tid1是细菌DnaJ和果蝇肿瘤抑制因子Tid56的人类同源物，具有两个选择性剪接的异构体，Tid1-长和-短（Tid1- l和-S），它们仅在羧基端不同。虽然Tid1蛋白绝大多数定位于线粒体，但已发表的数据主要显示非线粒体蛋白的相互作用和活性。本研究旨在确定Tid1蛋白是否作为线粒体dnaj样伴侣起作用，并解决主要针对线粒体的蛋白如何在非线粒体-线粒体途径中起作用的悖论。在这里，我们证明Tid1异构体表现出保守的线粒体dnaj样功能，取代酵母线粒体dnaj样蛋白Mdj1p。像Mdj1p一样，Tid1定位于人类线粒体类核，这是与线粒体DNA结合的大型蛋白质复合物。与其他DnaJs不同，Tid1-L和-S形成异质复合物；在人类细胞中可以观察到未组装的和复杂的Tid1。结果表明，与Tid1-S相比，Tid1-L在线粒体输入之前在细胞质中停留的时间更长；Tid1-L在细胞质中也明显比Tid1-S更稳定，后者被迅速降解。Tid1-L较长的细胞质停留时间和半衰期可以解释为它与细胞质Hsc70和潜在的蛋白质底物如STAT1和STAT3转录因子的相互作用。我们发现Tid1-L独特的羧基末端是与Hsc70、STAT1和-3相互作用所必需的。我们提出，Tid1与细胞质中伴侣和/或蛋白质底物的关联为Tid1在线粒体和非线粒体途径中的交替命运和功能提供了一种机制。
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 nonmito-chondrial 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 nonmito-chondrial 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 nonmito-chondrial pathways.