Abstract
Intermediate filaments (IFs) provide crucial structural support in higher eukaryotic cells. Accumulating evidences show that IFs also participate in various cellular activities including stress responses, cell growth, cell death and cell migration through dynamic interactions with various non-structure proteins. Here we report the identification of Pirh2, a RING-H2-type ubiquitin E3 ligase, as a novel binding partner of the cytoplasmic IF proteins keratin 8/18 (K8/18). Phosphorylation of either Pirh2 or K8/18 affects their association. Although Pirh2 was not found to influence the stability of K8/18, it displayed an unexpected role in regulating the organization of the network of K8/18 keratin filaments. Disruption of Pirh2–K8/K18 interaction by either UV irradiation or knockdown with Pirh2 or K18 led to the aggregation of K8/18 keratin filaments. It further induced mitochondrial redistribution, and this process is likely through a microtubule-mediated pathway. The abnormal localization of mitochondria in Pirh2-knockdown cells may partially account for its increased cell sensitivity to UV-induced apoptosis, probably through enhancing the release of pro-apoptotic proteins, such as cytochrome c and Smac/DIABLO to the cytosol. Overall, our data reveal the novel role of the Pirh2–K8/18 complex in governing the distribution of mitochondria.
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Abbreviations
- IFs:
-
intermediate filaments
- TRADD:
-
TNF receptor type 1-associated death domain protein
- JNK:
-
c-Jun N-terminal kinase
- TNF:
-
tumor necrosis factor
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Acknowledgements
We thank Dr. M Bishr Omary for providing plasmids encoding the keratin 8 cDNA. This research was supported by grants from the National Natural Science Foundation of China (30530200, 30728003 and 30871290), the Ministry of Science and Technology of China (2006AA02Z101, 2006CB933300 and 2006CB910300) and the Chinese Academy of Sciences (KSCX1-YW-R-57).
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Duan, S., Yao, Z., Zhu, Y. et al. The Pirh2–keratin 8/18 interaction modulates the cellular distribution of mitochondria and UV-induced apoptosis. Cell Death Differ 16, 826–837 (2009). https://doi.org/10.1038/cdd.2009.12
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DOI: https://doi.org/10.1038/cdd.2009.12
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