Out-of-frame start codons prevent translation of truncated nucleo-cytosolic cathepsin L in vivo

Martina Tholen, Larissa E. Hillebrand, Stefan Tholen, Oliver Sedelmeier, Sebastian J. Arnold and Thomas Reinheckel ()
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Martina Tholen: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg
Larissa E. Hillebrand: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg
Stefan Tholen: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg
Oliver Sedelmeier: Faculty of Biology, Albert-Ludwigs-University Freiburg
Sebastian J. Arnold: BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University
Thomas Reinheckel: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract The lysosomal protease cathepsin L has been reported to cleave various functionally important cytosolic or nuclear proteins. To explain nucleo-cytosolic localization of cathepsin L, it has been hypothesized that skipping of the first start codon during translation initiation results in an N-terminally truncated protein lacking the endoplasmic reticulum-import signal. Here we demonstrate that out-of-frame AUGs prevent translation of truncated cathepsin L in cell culture as well as in a new knock-in mouse model. We further evaluate potential roles of nuclear cathepsin L during early embryonic development. Our analysis reveals normal epiblast development of cathepsin L-deficient embryos, but uncovers a pronounced lysosomal storage phenotype in the extra-embryonic tissue of the visceral endoderm. In conclusion, the phenotypes of cathepsin L deficiency can be fully assigned to lack of canonically targeted cathepsin L, while the biogenesis and functionality of nucleo-cytosolic cathepsin L remain elusive.

Date: 2014
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DOI: 10.1038/ncomms5931

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