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First published online 24 June 2008
doi: 10.1242/jcs.021394

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eIF3k regulates apoptosis in epithelial cells by releasing caspase 3 from keratin-containing inclusions

¹ Institute of Biochemical Sciences, National Taiwan University, Taiwan
² Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
³ Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taiwan
⁴ Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan
⁵ Institute of Molecular and Cellular Biology and Department of Life Science, National Taiwan University, Taiwan

^* Author for correspondence (e-mail: rhchen{at}gate.sinica.edu.tw)

Accepted 30 April 2008

Keratins 8 and 18 (collectively referred to as K8/K18) are the major components of intermediate filaments of simple epithelial cells. Recent studies have revealed the function of K8/K18 in apoptosis modulation. Here, we show that eIF3k, originally identified as the smallest subunit of eukaryotic translation initiation factor 3 (eIF3) complexes, also localizes to keratin intermediate filaments and physically associates with K18 in epithelial cells. Upon induction of apoptosis, eIF3k colocalizes with K8/K18 in the insoluble cytoplasmic inclusions. Depletion of endogenous eIF3k de-sensitizes simple epithelial cells to various types of apoptosis through a K8/K18-dependent mechanism and promotes the retention of active caspase 3 in cytoplasmic inclusions by increasing its binding to keratins. Consequently, the cleavage of caspase cytosolic and nuclear substrates, such as ICAD and PARP, respectively, is reduced in eIF3k-depleted cells. This study not only reveals the existence of eIF3k in a subcellular compartment other than the eIF3 complex, but also identifies an apoptosis-promoting function of eIF3k in simple epithelial cells by relieving the caspase-sequestration effect of K8/K18, thereby increasing the availability of caspases to their non-keratin-residing substrates.

Key words: Keratin 8, Keratin 18, Caspase compartmentalization, Apoptosis, eIF3k

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