eIF3k regulates apoptosis in epithelial cells by releasing caspase 3 from keratin-containing inclusions.
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.
Lin
Yu-Min
YM
Institute of Biochemical Sciences, National Taiwan University, Taiwan.
Chen
Yi-Ru
YR
Lin
Jia-Ren
JR
Wang
Won-Jing
WJ
Inoko
Akihito
A
Inagaki
Masaki
M
Wu
Yi-Chun
YC
Chen
Ruey-Hwa
RH
D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology* / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D007106:Immune Sera; D002479:Inclusion Bodies / Q000201:enzymology*; D053538:Keratin-18 / Q000378:metabolism*; D053533:Keratin-8 / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D012995:Solubility; D013347:Subcellular Fractions / Q000378:metabolism
C468124:EIF3K protein, human; D007106:Immune Sera; D053538:Keratin-18; D053533:Keratin-8; D008869:Microtubule-Associated Proteins; D053148:Caspase 3