Type I keratins K18 and K19 undergo
caspase-mediated degradation during apoptosis. Two known
K18 caspase cleavage sites are aspartates in the consensus sequences VEVDA and DALDS, located within the rod domain and tail domain, respectively. Several K14 (another
type I keratin) mutations within the
caspase cleavage motif have been described in patients with
epidermolysis bullosa simplex. Here we use extensive mutational analysis to show that K19 and K14 are
caspase substrates and that the ability to undergo
caspase-mediated digestion of
K18, K19, or K14 is highly dependent on the location and nature of the mutation within the
caspase cleavage motif.
Caspase cleavage of K14 occurs at the
aspartate of VEMDA, a consensus sequence found in
type I keratins K12-17 with similar but not identical sequences in
K18 and K19. For
K18, apoptosis-induced cleavage occurs sequentially, first at (393)DALD and then at (234)VEVD. Hyperphosphorylation of
K18 protects from
caspase-3 in vitro digestion at (234)VEVD but not at (393)DALD. Hence,
keratins K12-17 are likely
caspase substrates during apoptosis.
Keratin hyperphosphorylation, which occurs early in apoptosis, protects from
caspase-mediated
K18 digestion in a cleavage site-specific manner. Mutations in
epidermolysis bullosa simplex patients could interfere with K14 degradation during apoptosis, depending on their location.